WO2004026235A2 - Compositions pharmaceutiques presentant une dissolution amelioree - Google Patents

Compositions pharmaceutiques presentant une dissolution amelioree Download PDF

Info

Publication number
WO2004026235A2
WO2004026235A2 PCT/US2003/028982 US0328982W WO2004026235A2 WO 2004026235 A2 WO2004026235 A2 WO 2004026235A2 US 0328982 W US0328982 W US 0328982W WO 2004026235 A2 WO2004026235 A2 WO 2004026235A2
Authority
WO
WIPO (PCT)
Prior art keywords
ofthe
composition
celecoxib
salt
pharmaceutical
Prior art date
Application number
PCT/US2003/028982
Other languages
English (en)
Other versions
WO2004026235A3 (fr
Inventor
Julius Remenar
Matthew Peterson
Om Almarsson
Hector Guzman
Hongming Chen
Mark Tawa
Mark Oliveira
Original Assignee
Transform Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Transform Pharmaceuticals, Inc. filed Critical Transform Pharmaceuticals, Inc.
Priority to AU2003267231A priority Critical patent/AU2003267231A1/en
Priority to US10/528,244 priority patent/US20060052432A1/en
Priority to EP10193736A priority patent/EP2339328A3/fr
Priority to PCT/US2003/041273 priority patent/WO2004061433A1/fr
Priority to EP03808567A priority patent/EP1579198A1/fr
Priority to CA2511881A priority patent/CA2511881C/fr
Priority to US10/541,216 priority patent/US8362062B2/en
Priority to AU2003303591A priority patent/AU2003303591A1/en
Priority to JP2005508617A priority patent/JP5021934B2/ja
Priority to AU2003300452A priority patent/AU2003300452A1/en
Priority to PCT/US2003/041642 priority patent/WO2004060347A2/fr
Publication of WO2004026235A2 publication Critical patent/WO2004026235A2/fr
Publication of WO2004026235A3 publication Critical patent/WO2004026235A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention relates to pharmaceutical compositions and methods for preparing same.
  • Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l- yl]benzenesulfonamide) is a substituted pyrazolylbenzenesulfonamide represented by the structure (I):
  • Celecoxib belongs to the general class of non-steroidal anti-inflammatory drugs (NSAIDs). Unlike traditional NSAIDs, celecoxib is a selective inhibitor of cyclooxygenase II (COX-2) that causes fewer side effects when administered to a subject.
  • COX-2 cyclooxygenase II
  • the synthesis and use of celecoxib are further described in U.S. Pat. Nos. 5,466,823, 5,510,496, 5,563,165, 5,753,688, 5,760,068, 5,972,986, 6,156,781, and 6,579,895, the contents of which are incorporated by reference in their entirety.
  • Orally deliverable liquid formulations of celecoxib are discussed in U.S. Patent Application Publication No. 2002/0107250 in the name of Hariharan, et al., the contents of which are incorporated herein by reference in their entirety.
  • Valdecoxib 4-(5-methyl-3-phenyl-4-isoxazolyl)benzene sulfonamide, is a substituted isoxazolyl benzenesulfonamide represented by the structural formula (II):
  • Valdecoxib also belongs to the general class of non-steroidal anti-inflammatory drugs (NSAIDs) and is another selective inhibitor of cyclooxygenase II (COX-2).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-2 cyclooxygenase II
  • the synthesis and use of valdecoxib are further described in U.S. Patent Nos. 5,633,272, 5,932,598, 5,985,902, 6,323,226, 6,384,034, 6,403,640 and 6,413,965, and U.S. Publication Nos. 2002/0013357, 2002/0015735, 2002/0034542, 2002/0071857, 2002/0107250 and 2002/0119193, the contents of which are incorporated herein by reference in their entirety.
  • COX-2 inhibitory drugs are related to celecoxib and valdecoxib, which form part of a larger group of drugs, all of which are benzene sulfonamides. These include: deracoxib, which is 4-[3-fluoro-4-methoxyphenyl)-3-difluoromethyl-lH- pyrazol-l-yl]benzene sulfonamide; rofecoxib, which is 3-phenyl-4-[- (methylsulfonyl)phenyl]-5H-furan-2-one; and etoricoxib, which is 5-chloro-3-(4- methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine. These drugs are described in further detail in WO 01/78724 and WO 02/102376.
  • celecoxib In its commercially available form, trademarked as CELEBREX, celecoxib is a neutral molecule that is essentially insoluble in water. Celecoxib typically exists as needle-like crystals, which tend to aggregate into a mass. Aggregation occurs even when celecoxib is mixed with other substances, such that a non-uniform mixture is obtained. These properties are shared by other pyrazolylbenzenesulfonamides and present significant problems in preparing pharmaceutical formulations ofthe drugs, particularly oral formulations.
  • Valdecoxib commercially available as BEXTRATM, is also a neutral molecule that is essentially insoluble in water.
  • Several strategies have been employed to increase the water solubility of valdecoxib, but these involve additional synthetic steps and the conversion of valdecoxib into a prodrug (e.g., through acylation).
  • An alternative strategy is to dissolve netural valdecoxib in an organic solvent (e.g., a glycol) and administer the valdecoxib-containing solution. It would be advantageous to provide new forms of drugs that have low aqueous dissolution which have improved properties, in particular as oral formulations.
  • API active pharmaceutical ingredient
  • the celecoxib and valdecoxib compositions ofthe present invention have a greater solubility, dissolution, total bioavailability (area under the curve or AUC), lower T max , the time to reach peak blood serum levels, and higher Cma ⁇ , > the maximum blood serum concentration, than their neutral counterparts.
  • the compositions ofthe present invention also include compounds that are less hygroscopic and more stable.
  • the salts ofthe present invention when in crystalline form convert to either an amorphous free form upon neutralization ofthe salt, which subsequently converts to a neutral metastable crystalline form or directly to a neutral metastable crystalline form.
  • These amorphous and metastable crystalline forms are more readily available forms ofthe API than are presently-marketed neutral celecoxib and valdecoxib.
  • Neutral crystalline celecoxib, presently-marketed as CELEBREXTM, and neutral crystalline valdecoxib, presently-marketed as BEXTRATM, are designated as "neutral" to distinguish from the ionized salt forms ofthe APIs.
  • An aspect of the present invention relates to methods of increasing dissolution, solubility, and or the time an API (either alone or as part of a pharmaceutical composition), can be maintained, upon dissolution, as a supersaturated solution, before precipitating out of solution.
  • the increase in dissolution results in, and thus can be represented by an increase in bioavailability, AUC, reduced time to T max or increased C max .
  • the methods comprise the steps of making a salt or co-crystal from an API (e.g. free acid) and combining the salt or co-crystal with a precipitation retardant and optionally, a precipitation retardant enhancer (referred to as enhancer hereafter).
  • a precipitation retardant e.g. free acid
  • enhancer a precipitation retardant enhancer
  • the term “precipitation” refers to either a crystalline or amorphous solid form separating or "coming out of the solution.
  • the salt may be amorphous or crystalline, but is preferably crystalline. Normally the salt or co-crystal form used is in a crystalline form that dissolves and then recrystallizes and precipitates out of solution, which is why the term “crystallization" retardant may be used in place of "precipitation” for greater specificity.
  • crystalline salts are superior to amorphous salts as the initial compound, with an amorphous salt being superior to a neutral amorphous or crystalline form.
  • Free acid forms are not preferred initial compounds unless first solubilized in a solubilizer resulting in a liquid formulation comprising a precipitation retardant and optional enhancer.
  • the precipitation retardant is often a surfactant, preferably a surfactant with an ether functional group, preferably a repeating ether group, e.g., an ether group repeated at least two or three times wherein the oxygen atoms are separated by 2 carbon atoms.
  • Further preferred surfactants have an interfacial tension of less than 10 dynes per centimeter when measured at a concentration of 0.1 %w/w in water at 25 degrees C and/or the surface tension ofthe precipitation retardant (e.g., poloxamers) is less than 42 dynes/cm when measured as a concentration of 0.1 %w/w in water at 25 degrees C.
  • the combination of salt or co-crystal, precipitation retardant and an optional enhancer preferably prevents or delays precipitation of a supersaturated solution by about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes or greater than 1 hour in an aqueous solution, preferably water or gastric fluid conditions such as the gastric fluids of an average human stomach fasted for 12 hours or simulated gastric fluid (SGF).
  • a supersaturated solution by about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes or greater than 1 hour in an aqueous solution, preferably water or gastric fluid conditions such as the gastric fluids of an average human stomach fasted for 12 hours or simulated gastric fluid (SGF).
  • SGF simulated gastric fluid
  • the SGF may be diluted by 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold to represent water intake.
  • the SGF may be diluted 5 fold to represent a patient drinking a glass of water at the time a composition ofthe present invention is taken orally.
  • the degree of increase in solubility, dissolution, and/or supersaturation may be specified, 'such as by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 fold greater than thefree acid in the same solution.
  • the increase in dissolution may be further specified by the time the composition remains supersaturated.
  • the enhancer preferably comprises a cellulose ester such as hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC).
  • HPC hydroxypropylcellulose
  • HPMC hydroxypropylmethylcellulose
  • the enhancer does not improve or only minimally improves (less than/equal to 10%) the length of time the API can remain supersaturated without the additional presence ofthe precipitation retardant.
  • the methods ofthe present invention are used to make a pharmaceutical drug formulation with greater solubility, dissolution, and bioavailability, AUC, reduced time to T max , the time to reach peak blood serum levels, and higher Cmax,, the maximum blood serum concentration, when compared to the neutral form or salt alone.
  • AUC is the area under the plot of plasma concentration of drug (not logarithm ofthe concentration) against time after drug administration. The area is conveniently determined by the "trapezoidal rule": the data points are connected by straight line segments, perpendiculars are erected from the abscissa to each data point, and the sum ofthe areas of he triangles and trapezoids so constructed is computed.
  • the AUC from t n to infinite time is estimated by C n /k e i.
  • the AUC is of particular use in estimating bioavailability of drugs, and in estimating total clearance of drugs (Cl ⁇ ).
  • AUC F • D/Cl ⁇ , where F is the absolute bioavailability ofthe drug.
  • the invention further relates to wherein a precipitation retardant and an optional enhancer is combined with a pharmaceutical that is already in a salt or co-crystal form.
  • the invention further relates to wherein a precipitation retardant and an optional enhancer is combined with a pharmaceutical that is a solvate, desolvate, hydrate, dehydrate, or anhydrous form of a salt or co-crystal form.
  • the present invention provides a pharmaceutical composition comprising:
  • the present invention provides a pharmaceutical composition comprising:
  • the present invention provides a pharmaceutical composition comprising:
  • the present invention provides a pharmaceutical composition comprising:
  • the present invention provides a pharmaceutical composition comprising:
  • the present invention provides a pharmaceutical composition comprising:
  • HPC hydroxypropylcellulose
  • HPMC hydroxypropylmethylcellulose
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) an API having low aqueous solubility or dissolution, preferably in gastric fluid conditions;
  • hydroxypropylcellulose HPC
  • HPMC hydroxypropylmethylcellulose
  • hydroxypropylcellulose HPC
  • HPMC hydroxypropylmethylcellulose
  • a poloxamer surfactant having an interfacial tension at a concentration of 0.1% of less than 10 dyne/cm or surface tension less then 42 dyne/cm; and (c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose
  • the present invention provides a process for producing a pharmaceutical composition for delivering a supersaturated concentration of a drug having low aqueous dissolution, preferably in gastric fluid conditions, which comprises intimately mixing together the components ofthe above aspects or elsewhere herein.
  • the surfactant is at a concentration of less than 5 %, 4 %, 3 %, 2 %, 1 %, 0.9 %, 0.8 %, 0.7 %, 0.6 %, 0.5 %, 0.4 %, 0.3 %, 0.2 %, or 0.1 % or at a concentration of 0.1 % (w/w).
  • the present invention further provides a process for producing a pharmaceutical composition, which comprises:
  • solid-state nucleation is used herein to refer to the initiation of solidification, whether amorphous or crystalline, but may be specified as being amorphous or crystalline.
  • excipients or other properties ofthe combination can be chosen for the production of a pharmaceutical composition in which the API remains in solution for a sufficient time after administration to a subject.
  • pharmaceutical compositions which attain at least a minimum bioavailability of the API may be readily produced based on a straightforward in vitro screening.
  • compositions may affect the onset of solid-state nucleation or precipitation of the API .
  • properties include the identity or amount ofthe excipient and the identity or amount ofthe pharmaceutical compound in the composition.
  • Other properties may include the amount of other diluents or carriers such as salts or buffering compounds.
  • the pharmaceutical compound itself may be screened in a variety of different forms if it is capable of polymorphism. Additionally, different salt, solvate, hydrate, co-crystal and other forms of the API may be screened in accordance with the invention. The invention is readily applicable to screening a large variety of different excipients. Accordingly, in a preferred aspect, the present invention provides a process for producing a pharmaceutical composition, which comprises:
  • excipient which is varied. Different excipients may be used in different containers and may be present as a single excipient or in a combination of a plurality of excipients, for example, a binary, ternary, tertiary or higher order combination.
  • the present invention provides a pharmaceutical composition obtained by processes according to the invention.
  • the pharmaceutical composition may comprise a further excipient, diluent or carrier.
  • the pharmaceutical composition is formulated for oral administration.
  • the invention further provides a method for assessing excipient-mediated retardation of solid-state nucleation or precipitation of a pharmaceutical compound, which method comprises:
  • the present invention provides a method for screening excipients that retard solid-state nucleation or precipitation of a pharmaceutical compound, which method comprises:
  • the active pharmaceutical ingredient is typically capable of existing as a supersaturated solution, preferably in an aqueous-based medium.
  • the API may be a free acid, free base, co-crystal or salt, or a solvate, hydrate or dehydrate thereof.
  • the invention is particularly applicable to pharmaceutical compositions comprising an API which, when in contact with a body fluid such as gastric juices or intestinal fluids, would be likely to precipitate or crystallize from solution in a nucleation event. Accordingly, the invention is particularly applicable to pharmaceutical compounds which may have relatively low solubility, or dissolution, as defined herein, when in contact with bodily fluids but possibly relatively high solubility, or dissolution, in appropriate in vitro conditions.
  • the compound solution is a solution wherein the compound is solubilized and may be a non-aqueous solution or an aqueous solution with a pH adjusted to accommodate the compound.
  • a free base-type compound would be dissolved in aqueous solution at acidic pH whereas a free acid-type compound would be dissolved in an aqueous solution of basic pH.
  • the compound solution may therefore be, and preferably is, a supersaturated solution when compared to water, gastric fluids or intestinal fluids. It would also be preferred for the excipient to be in a solution comprising water, usually deionised water, or another aqueous based solution.
  • the mixture simulates gastric fluid (SGF) or intestinal fluids (SIF, 0.68% monobasic potassium phosphate, 1% pancreatin, and sodium hydroxide where the pH ofthe final solution is 7.5.) and in this aspect it is preferred that the excipient is added in a solution simulating those body fluids. Alternatively, further additives, usually in solution, may be added to form the mixtures creating an environment appropriate for the screening to be undertaken.
  • SGF gastric fluid
  • SIF intestinal fluids
  • the excipient is added in a solution simulating those body fluids.
  • further additives usually in solution, may be added to form the mixtures creating an environment appropriate for the screening to be undertaken.
  • One advantage ofthe present invention is that the plurality of containers may be presented in a multiple well plate format or block and tube format such that at least 24, 48, 96, 384, or 1536 samples are assayed in parallel.
  • Multiple block and tubes or multiwell plates maybe assayed such that at least 1000, 3000, 5000, 7000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, or 100000 total samples are assayed.
  • This is advantageous because the process may be operated in a semi- automated or automated way using existing multiple well plate format-based apparatus. At least the step of dispensing may be performed with automated liquid handling apparatus. Accordingly, it is possible to operate the process as a high throughput screen. Additionally, using a multiple well plate format, the scale ofthe screening is relatively low.
  • each sample may contain less than 100 mg, 50mg, 25mg, 10, mg, 5 mg, 750 microg, 500 microg, 250, microg, 100 microg, 75 microg, 50 microg, 25 microg, 10 microg, 1 microg, 750ng, 500ng, 250ng, lOOng, or less than 50ng, depending on the API, sample size, etc.
  • This therefore, minimizes the amount of API which is needed to identify excipients or properties ofthe combination of pharmaceutical compound and excipient that retard onset of nucleation. In this way, improved speed and relatively low cost are advantages.
  • the intimate mixture formed in the process may be achieved by any conventional method, including the use of a mixer during or after dispensing ofthe solutions. Once the mixture has been formed, it is generally advantageous to incubate the mixture at a constant temperature, such as approximately 37 degrees C, to simulate in vivo conditions.
  • Measurement of onset of solid-state nucleation or precipitation may be determined for example, by measuring the light scattering of a mixture. This may be achieved by any conventional light scattering measurement, such as the use of a nephelometer. It is also possible to include a further step in which the crystallinity of the products ofthe solid-state nucleation or precipitation is determined. This step is conveniently performed before selecting the pharmaceutical compound/excipient combination for use in the pharmaceutical composition. Crystallinity may be determined, e.g., by birefringence screening.
  • Neither the light scattering measurement nor the birefringence screening are invasive measurement techniques.
  • a portion or all ofthe sample solution does not need to be transferred to a second container and the containers or wells can be sealed with a transparent seal to allow use of these techniques.
  • the present invention relates to a pharmaceutical composition which includes an API having a low aqueous solubility or dissolution (as defined herein).
  • low aqueous solubility in the present application refers to a compound having a solubility in water which is less than or equal to 10 mg/mL, when measured at 37 degrees C, and preferably less than or equal to 1 mg/mL.
  • the invention relates more particularly to drugs which have a solubility of not greater than 0.1 mg/mL.
  • the invention further relates to compounds that cannot be maintained as a supersaturated solution in gastric or intestinal fluid or in SGF or SIF.
  • Such drugs include some sulfonamide drugs, such as the benzene sulfonamides, particularly those pyrazolylbenzenesulfonamides discussed above, which include COX-2 inhibitors.
  • sulfonamide drugs such as the benzene sulfonamides, particularly those pyrazolylbenzenesulfonamides discussed above, which include COX-2 inhibitors.
  • stable crystalline metal salts of pyrazolylbenzenesulfonamides such as celecoxib and valdecoxib.
  • Such metal salts include alkali metal or alkaline earth metal salts, preferably sodium, potassium, lithium, calcium and magnesium salts. It is preferred that the pharmaceutical composition is formulated for oral administration.
  • Drugs according to the invention may be prepared in a form having reduced time to onset of therapeutic effectiveness (the time when an effect for which the drug is administered can be identified or measured, e.g., the point in time when a reduction in fever or pain felt by a patient begins to occur) or increased bioavailability.
  • the pharmaceutical compositions according to the invention are therefore particularly suitable for administration to human subjects.
  • Fig. 1 shows a differential scanning calorimetry (DSC) thermogram ofthe sodium salt of celecoxib prepared by Example 1 between 50 degrees C and 110 degrees C.
  • Fig. 2 shows a thermogravimetric analysis (TGA) thermogram ofthe sodium salt of celecoxib prepared by Example 1, which was conducted from about 30 degrees C to about 160 degrees C.
  • TGA thermogravimetric analysis
  • Fig. 3 shows a PXRD diffractogram ofthe sodium salt of celecoxib prepared by Example 1.
  • Figs. 4A and 4B show pharmacokinetics in male Sprague-Dawley rats after 5 mg kg oral doses ofthe celecoxib crystal form used in the marketed formulations and the sodium salt of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l- yljbenzenesulfonamide, as obtained following the protocol described in Example 4.
  • Fig. 5 shows the mean pharmacokinetic parameters (and standard deviations therefor) of celecoxib in the plasma of male dogs following a single oral or single intravenous dose of celecoxib or celecoxib sodium.
  • the maximum serum concentration and bioavailability of orally-administered celecoxib sodium was about three- and two-fold greater, respectively, than a roughly equal dose of orally- administered celecoxib, and the maximum serum concentration of celecoxib sodium was reached 40% faster than for celecoxib.
  • Fig. 6 shows the mean concentrations of celecoxib in plasma following the administration of a single oral dose of celecoxib or celecoxib sodium or a single intravenous dose of celecoxib in male dogs.
  • Fig. 7 shows the effect of varying ratios of ethylene glycol to propylene glycol subunits in poloxamers on the concentration of celecoxib sodium in solution.
  • Fig. 8 shows the effect of different celluloses on the dissolution of various composition
  • cellulose hydroxypropylcellulose (HPC, 100,000 kDa), low- viscosity hydroxypropylmethylcellulose (Id HPMC, viscocity was 80-120 cps), high-viscosity hydroxypropylmethylcellulose (hd HPMC, viscosity was 15,000 cps), microcrystalline cellulose (Avicel PH200)), d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TGPS), and celecoxib sodium.
  • HPC hydroxypropylcellulose
  • Id HPMC low- viscosity hydroxypropylmethylcellulose
  • hd HPMC high-viscosity hydroxypropylmethylcellulose
  • microcrystalline cellulose Avicel PH200
  • d-alpha-tocopherol polyethylene glycol-1000 succinate vitamin E TGPS
  • celecoxib sodium celecoxib sodium
  • Fig. 9 shows the dissolution at 37 degrees C for compositions comprising various weight ratios of d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TGPS), hydroxypropylcellulose and celecoxib sodium.
  • Fig. 10 shows the dissolution profile of celecoxib sodium in simulated gastric fluid (SGF) from solid mixtures with excipients at room temperature.
  • the legend indicates the excipient and the weight ratio of excipient to celecoxib sodium (if unmarked, 1:1).
  • Excipients include polyvinylpyrrolidone (PVP), poloxamer 188 (P188), poloxamer 237 (P237), d-alpha-tocopherol polyethylene glycol-1000 succinate (vit E TGPS), and GelucireTM 50/13.
  • Fig. 11 shows the effect of Avicel microcrystalline cellulose and silica gel on the dissolution of mixtures of celecoxib sodium, d-alpha-tocopherol polyethylene glycol-1000 succinate (vit E TGPS), and hydroxypropylcellulose (HPC) mixtures in simulated gastric fluid (SGF) at 37 degrees C.
  • the legend indicates the weight ratios of the components.
  • Fig. 12 shows the dissolution of celecoxib sodium in 5-times diluted simulated gastric fluid, with excipients including d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TGPS), hydroxypropylcellulose (HPC), and poloxamer 237.
  • the legend indicates the weight ratios ofthe components.
  • Figs. 13 A and 13B show the PXRD diffractogram and Raman spectrum, respectively, ofthe sodium salt of celecoxib prepared by the method of Example 6.
  • Fig. 14 shows a differential scanning calorimetry (DSC) thermogram of celecoxib lithium salt MO-116-49B.
  • Fig. 15 shows a thermogravimetric analysis (TGA) thermogram of celecoxib lithium salt MO-116-49B.
  • Fig. 16 shows the RAMAN spectrum of celecoxib lithium salt MO-116-49B.
  • Fig. 17 shows the PXRD diffractogram of celecoxib lithium salt MO-116-49B.
  • Fig. 18 shows a differential scanning calorimetry (DSC) thermogram of celecoxib potassium salt MO-116-49A.
  • Fig. 19 shows a thermogravimetric analysis (TGA) thermogram of celecoxib potassium salt MO-116-49A.
  • Fig. 20 shows the RAMAN spectrum of celecoxib potassium salt MO-116-49A.
  • Fig. 21 shows the PXRD diffractogram of celecoxib potassium salt MO-116- 49A.
  • Fig. 22 shows a thermogravimetric analysis (TGA) thermogram of celecoxib potassium salt MO-116-55D.
  • Fig. 23 shows the RAMAN spectrum of celecoxib potassium salt MO-116-55D.
  • Fig. 24 shows the PXRD diffractogram of celecoxib potassium salt MO-116- 55D.
  • Fig. 25 shows a thermogravimetric analysis (TGA) thermogram of celecoxib calcium salt MO-116-62A.
  • Fig. 26 shows the RAMAN spectrum of celecoxib calcium salt MO-116-62 A.
  • Fig. 27 shows the PXRD diffractogram of celecoxib calcium salt MO- 116-62 A.
  • Fig. 28 shows the PXRD diffractogram of commercially-available celecoxib.
  • Fig. 29 shows the RAMAN spectrum of commercially-available celecoxib.
  • Fig. 30 shows crystal retardation time for celecoxib as a function of excipient in simulated gastric fluid (SGF).
  • Fig. 31 shows interfacial tension of selected PLURONIC excipients in water.
  • Fig. 32 shows dissolution of celecoxib sodium hydrate from compositions containing PLURONIC P123 and F127.
  • Fig. 33 shows dissolution of celecoxib sodium hydrate from PLURONIC PI 23, F127 and F87, in the presence of HPC.
  • Fig. 34 shows dissolution of celecoxib sodium hydrate using PLURONIC F127, HPC and a granulating fluid.
  • Fig. 35 shows dissolution of celecoxib sodium hydrate using PLURONIC F127 and HPC in a compact formulation.
  • Fig. 36 shows a flowchart outlining a process according to the invention.
  • Fig. 37 shows a platemap for an automated liquid dispenser.
  • Fig. 38 shows a trace of light scatter against time in an assay according to the invention.
  • Fig. 39 shows a thermogravimetric analysis (TGA) thermogram of a propylene glycol solvate of a celecoxib sodium salt.
  • Fig. 40 shows the PXRD diffractogram of a propylene glycol solvate of a celecoxib sodium salt.
  • Fig. 41 shows a thermogravimetric analysis (TGA) thermogram of a propylene glycol solvate of a celecoxib potassium salt.
  • Fig. 42 shows the PXRD diffractogram of a propylene glycol solvate of a celecoxib potassium salt.
  • Fig. 43 shows a thermogravimetric analysis (TGA) thermogram of a propylene glycol solvate of a celecoxib lithium salt.
  • Fig. 44 shows a thermogravimetric analysis (TGA) thermogram ofthe sodium salt propylene glycol trihydrate of celecoxib prepared by Example 21.
  • Fig. 45 shows a PXRD diffractogram ofthe sodium salt propylene glycol trihydrate of celecoxib prepared by Example 21a.
  • Fig. 46 shows a thermogravimetric analysis (TGA) thermogram ofthe sodium salt propylene glycoltrihydrate of celecoxib prepared by Example 21b.
  • Fig. 47 shows a PXRD diffractogram ofthe sodium salt propylene glycol trihydrate of celecoxib prepared by Example 21b.
  • Fig. 48 shows a differential scanning calorimetry (DSC) thermogram ofthe sodium salt isopropyl alcohol solvate of celecoxib prepared by Example 22.
  • Fig. 49 shows a thermogravimetric analysis (TGA) thermogram ofthe sodium salt isopropyl alcohol solvate of celecoxib prepared by Example 22, which was conducted from about 30° to about 160 degrees C.
  • TGA thermogravimetric analysis
  • Fig. 50 shows a PXRD diffractogram ofthe isopropyl alcohol solvate of celecoxib sodium salt prepared by Example 22.
  • Fig. 51 shows a PXRD diffractogram ofthe propylene glycol solvate of celecoxib lithium salt prepared by Example 20.
  • Fig. 52 shows a PXRD diffractogram ofthe celecoxibmicotinamide co-crystals prepared by Example 23.
  • Fig. 53 shows a PXRD diffractogram ofthe hydrate of celecoxib sodium salt under 17 % RH prepared by Example 24.
  • Fig. 54 shows a PXRD diffractogram ofthe hydrate of celecoxib sodium salt under 31 % RH prepared by Example 24.
  • Fig. 55 shows a PXRD diffractogram ofthe hydrate of celecoxib sodium salt under 59 % RH prepared by Example 24.
  • Fig. 56 shows a PXRD diffractogram ofthe hydrate of celecoxib sodium salt under 74 % RH prepared by Example 24.
  • Fig. 57 shows a PXRD diffractogram ofthe hydrate ofthe propylene glycol solvate of celecoxib sodium salt under 17 % RH prepared by Example 24.
  • Fig. 58 shows a PXRD diffractogram ofthe hydrate ofthe propylene glycol solvate of celecoxib sodium salt under 31 % RH prepared by Example 24.
  • Fig. 59 shows a PXRD diffractogram ofthe hydrate ofthe propylene glycol solvate of celecoxib sodium salt under 59 % RH prepared by Example 24.
  • Fig. 60 shows a PXRD diffractogram ofthe hydrate ofthe propylene glycol solvate of celecoxib sodium salt under 74 % RH prepared by Example 24.
  • Fig. 61 shows PXRD diffractograms of multiple celecoxib sodium salt samples with various hydration states prepared by Example 25.
  • Fig. 62 shows a DSC thermogram of valdecoxib isopropanol solvate prepared by Example 26.
  • Fig. 63 shows a TGA thermogram of valdecoxib isopropanol solvate prepared by Example 26.
  • Fig. 64 shows a PXRD diffractogram of valdecoxib isopropanol solvate prepared by Example 26.
  • Fig. 65 shows a Raman spectrum of valdecoxib isopropanol solvate prepared by Example 26.
  • Fig. 66 shows a *H NMR spectrum of valdecoxib isopropanol solvate prepared by Example 26.
  • Fig. 67 shows a DSC thermogram of valdecoxib sodium salt prepared by Example 27.
  • Fig. 68 shows a TGA thermogram of valdecoxib sodium salt prepared by Example 27.
  • Fig. 69 shows a PXRD diffractogram of valdecoxib sodium salt prepared by Example 27.
  • Fig. 70 shows a Raman spectrum of valdecoxib sodium salt prepared by Example 27.
  • Fig. 71 shows an ⁇ NMR spectrum of valdecoxib sodium salt prepared by
  • the present invention relates to a pharmaceutical composition that includes an API having a low aqueous solubility, e.g., in gastric fluid conditions.
  • low aqueous solubility in the present application refers to a compound having a solubility in water which is less than or equal to lOmg/mL, when measured at 37 degrees C, and preferably less than or equal to 5mg/mL or lmg/mL.
  • Low aqueous solubility can further be defined as less than or equal to 900, 800, 700, 600, 500, 400, 300, 200 150 100, 90, 80, 70, 60, 50, 40, 30, 20 micrograms/mL, or further 10, 5 or 1 micrograms/mL, or further 900, 800, 700, 600, 500, 400, 300, 200 150, 100 90, 80, 70, 60, 50, 40, 30, 20, or 10 ng/mL, or less than 10 ng/mL when measured at 37 degrees C. Further aqueous solubility can be measured in simulated gastric fluid (SGF) rather than water.
  • SGF simulated gastric fluid
  • the pH ofthe solution may also be specified as 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12.
  • APIs which have a solubility of not greater than 0.1 mg/mL, including some sulfonamide drugs, such as the benzene sulfonamides, particularly those pyrazolylbenzenesulfonamides discussed above, which include COX-2 inhibitors, are included in the present invention.
  • sulfonamide drugs such as the benzene sulfonamides, particularly those pyrazolylbenzenesulfonamides discussed above, which include COX-2 inhibitors
  • sulfonamide drugs such as the benzene sulfonamides, particularly those pyrazolylbenzenesulfonamides discussed above, which include COX-2 inhibitors
  • stable crystalline metal salts and co-crystals of pyrazolylbenzenesulfonamides such as celecoxib and valdecoxib.
  • Such metal salts include alkali metal or alkaline earth metal salts, preferably sodium, potassium, lithium, calcium and magnesium
  • an API with low aqueous solubility is formulated with a precipitation retardant and, optionally, with a precipitation retardant enhancer.
  • the precipitation retardant used in the present invention can be chosen from a wide range of surfactants (see e.g., Fig. 30). Embodiments include where the surfactant is non-ionic or where the surfactant is ionic.
  • the interfacial tension ofthe precipitation retardant is less than 10 dyne/cm when measured as a concentration of 0.1 % w/w in water as compared to mineral oil at 25 degrees C and/or the surface tension ofthe precipitation retardant (e.g., poloxamers) is less than 42 dyne/cm when measured as a concentration of 0.1 % w/w in water.
  • the interfacial tension is less than 15, 14, 13, 12, 11, 10, 9, 8, 7, or 6 dyne/cm or the surface tension is less than 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, or 35 dyne/cm.
  • the surfactant is a poloxamer.
  • a poloxamer comprises an ethylene oxide-propylene oxide block copolymer, which preferably has the structure (PEG) x -(PPG) y -(PEG) z , where x, y and z are integers and x is usually equal to z.
  • Preferred forms of poloxamers are those obtainable from BASF, as trademarked PLURONIC.
  • PLURONIC poloxamers examples include PLURONIC L122, PLURONIC P123, PLURONIC F127 (Poloxamer 407), PLURONIC L72, PLURONIC P105, PLURONIC LP2, PLURONIC P104, PLURONIC F108 (Poloxamer 338), PLURONIC P103, PLURONIC L44 (Poloxamer 124), PLURONIC F68 (Poloxamer 188), and PLURONIC F87 (Poloxamer 237).
  • a specific poloxamer and its corresponding PLURONIC i.e., the generic and tradename, may be used interchangeably throughout.
  • the invention provides a pharmaceutical composition comprising: (a) an API; and
  • a polyether block copolymer comprising an A-type linear polymeric segment joined at one end to a B-type linear polymeric segment, wherein the A-type segment is of relatively hydrophilic character, the repeating units of which contribute an average Hansch-Leo fragmental constant of about -0.4 or less and have molecular weight contributions between about 30 and about 500, wherein the B-type segment is of relatively hydrophobic character, the repeating units of which contribute an average Hansch-Leo fragmental constant of about -0.4 or more and have molecular weight contributions between about 30 and about 500, wherein at least about 80% ofthe linkages joining the repeating units for each ofthe polymeric segments comprise an ether linkage.
  • the polyether block copolymer is selected from the group consisting of polymers of formulas:
  • a and A' are A-type linear polymeric segments
  • B and B' are B-type linear polymeric segments
  • R 1 , R 2 , R 3 and R 4 are either block copolymers of formulas (III), (IV) or (V) or hydrogen and L is a linking group, with the proviso that no more than two of R 1 , R 2 , R 3 or R 4 are hydrogen.
  • the composition includes micelles ofthe block copolymer or forms micelles ofthe block copolymers during the course of administration or subsequent thereto.
  • at least about 0.1 % ofthe biological agent is inco ⁇ orated in the micelles, more preferably, at least about 1 % of the biological agent, yet more preferably, at least about 5 % ofthe biological agent.
  • the hydrophobic percentage ofthe copolymer ofthe composition is at least about 50 % more preferably, at least about 60 %, yet more preferably 70 %.
  • the hydrophobic weight ofthe copolymer is at least about 900, more preferably, at least about 1700, yet more preferably at least about 2000, still more preferably at least about 2300.
  • the hydrophobic weight is at least about 2000 and the hydrophobic percentage is at least about 20 %, preferably 35 %; or the hydrophobic weight is at least about 2300 and the hydrophobic percentage is at least about 20 %, preferably 35 %.
  • the optional third component ofthe pharmaceutical composition according to the present invention comprises a precipitation retardant enhancer.
  • An enhancer is a compound capable of increasing the effectiveness of the precipitation retardant in inhibiting, preventing or at least reducing the extent of precipitation of a drug of low aqueous solubility, usually when diluted such as following oral administration.
  • the enhancer does not act as a precipitation retardant alone.
  • the enhancer has no effect or a negative effect in an in vitro precipitation assay, but increases the effectiveness ofthe precipitation retardant in an in vivo or in vitro dissolution assay.
  • Cellulose esters, such as hydroxypropyl cellulose, are particularly useful enhancers according to the present invention.
  • Cellulose esters vary in the chain length of their cellulosic backbone and consequently, vary in their viscosities as measured for example at a 2% by weight concentration in water at 20 degrees C. Lower viscosities are normally preferred to higher viscosities in the present invention.
  • the cellulose ester such as HPC, has a viscosity, 2% in water, of about 100 to about 100,000 cP or about 1000 to about 15,000 cP. In other embodiments the viscosity is less than 1,500,000, 1,000,000, 500,000, 100,000, 75,000, 50,000, 35,000, 25,000, 20,000, 17,500, 15,000, 12,500.
  • Enhancers are also useful in delaying the T max and/or increasing the amount of time the API concentration is above V. T max , thus acting to smooth out a curve of blood serum concentration vs. time.
  • Preferred enhancers increase the amount of time the API concentration is above l A T max by 25%, 50%, 75%, 100%, three fold or more than three fold.
  • the composition has both a reduced time to T max and remains at l A T max longer than the free acid or in the same composition except the salt or co-crystal is replaced by the free acid.
  • the ratio of component a:b:c is approximately 1:1:1 (+/- 0.2 for the precipitation retardant and enhancer). However, the ratio can be adjusted to suit the application. For example, the amount of precipitation retardant or enhancer may need to be decreased, and even decreased below the optimum concentration in order to decrease the amount of excipients in the administered form ofthe composition, such as a tablet or capsule.
  • the unit dosage form comprises an amount of precipitation retardant (surfactant) that is at or above an amount needed for the retardant to reach its critical micell concentration (CMC) in H 2 0 or SGF. It is noted the poloxamers may not form true micells but do form analogous structures which are considered micells for the purpose ofthe present invention.
  • the composition may further comprise a pharmaceutically-acceptable diluent, excipient or carrier and such additional components are discussed in further detail below.
  • a pharmaceutically-acceptable diluent, excipient or carrier and such additional components are discussed in further detail below.
  • One such additional component comprises a granulating fluid-like liquid, such as poloxamer 124, PEG 200 or PEG 400, that forms an intimate contact between the API, precipitation retardant and optional enhancer by binding or partially dissolving them.
  • the composition remains in a solid, semi-solid or paste, although an embodiment is drawn to wherein the composition is at least 25%, 50%, 75% or nearly or fully dissolved Any pharmaceutically acceptable liquid may be used as long as it does not cause conversion ofthe salt or co-crystal form to the free form in the solid state.
  • Some non-limiting examples include methanol, ethanol, isopropanol, higher alcohols, propylene glycol, ethyl caprylate, propylene glycol laurate, PEG, diethyl glycol monoethyl ether (DGME), tetraethylene glycol dimethyl ether, triethylene glycol monoethyl ether, and polysorbate 80.
  • the presence ofthe granulating fluid-like liquid increases the dissolution of the API, possibly by delaying the contact between the API and the dissolution medium until the surfactant dissolves to a significant extent, thus delaying precipitation.
  • the use of a granulating fluid-like liquid is particularly useful when the API and precipitation retardant are solids.
  • the pharmaceutical composition is in the form of a compact whereby, during the process of producing the pharmaceutical composition, the components are compacted together. Compaction may perform a similar role to that performed by the granulating fluid. Retarded dissolution or a smoothing out ofthe curve of blood serum concentration vs. time may be limited, if required, by using a disintegrant in the compact.
  • the API and precipitation retardant (and optional enhancer) forms a paste or non-aqueous solution when mixed. An adherent mass of components may be produced if a paste is used, which is thought to delay dissolution of the API by allowing the surfactant to dissolve first. This is thought to promote supersaturation ofthe API.
  • the compounds ofthe present invention are intimately associated as a pharmaceutical composition.
  • An "intimate association" in the present context includes, for example, the pharmaceutical admixed with the precipitation retardant, the pharmaceutical embedded or incorporated in the retardant, the compound forming a coating on particles ofthe pharmaceutical or vice versa, and a substantially homogeneous dispersion ofthe pharmaceutical throughout the compounds.
  • the pharmaceutical composition includes a COX-2 inhibitor
  • a method of treating a subject in a further aspect ofthe invention, in which the subject may be suffering from pain, inflammation, cancer or pre-cancer such as intestinal or colonic polyps.
  • the method comprises administering to the subject a pharmaceutical composition as described herein.
  • the pharmaceutical composition is formulated for oral administration.
  • Drugs according to the invention may be prepared in a form having a decreased time to onset of therapeutic effectiveness and an increased bioavailability.
  • the pharmaceutical compositions according to the invention are particularly suitable for administration to human subjects.
  • the methods and compositions ofthe present invention relate to improving solubility, dissolution and bioavailability of pharmaceuticals.
  • the present invention further relates to improving the performance of pharmaceutical compounds that initially dissolve but then precipitate or recrystallize in gastric fluid conditions.
  • Further embodiments relate to pharmaceuticals with an aminosulfonyl functional group .
  • aminosulfonyl functional group herein refers to a functional group having the following structure (VII):
  • the wavy line represents a bond by which the functional group is attached to the rest ofthe drug molecule; and R is hydrogen or a substituent that preserves ability of polyethylene glycol or a polyethylene glycol degradation product to react with the amino group adjacent to R to form an addition compound.
  • substituents include partially unsaturated hereocyclyl, hereoaryl, cycloalkenyl, aryl, alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, phenyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, hydroxyl, alkoxyalkyloxyalkyl, haloalkylsulfonyloxy, carboxyalkoxyalkyl, cycloalkylalkyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, heteroarylcarbonyl, alkylthioalkyl, arylcarbonyl, alkylthioalkyl, arylcarbonyl, alky
  • Non-limiting illustrative examples of aminosulfonyl-comprising drugs include ABT-751 of Eisai (N-(2-(4-hydroxyphenyl)ammo)-3-pyridyl)4- methoxybenzenesulfonamide); alpiropride; amosulalol; amprenavir; amsacrine; argatroban; asulacrine; azosemide; BAY-38-4766 of Bayer (N-[4-[[[5- (dimethylamino)-l-naphthalenyl]sulfonyl]amino]phenyl]-3-hyrdroxy-2,2- dimethylpropanamide); bendroflumethiazide; BMS-193884 of Bristol Myers Squibb (N-(3,4-dimethyl-5-isoxazolyl)-4 1 -(2-oxazolyl)-[l,l 1 -biphenyl]-2
  • the aminosulfonyl-comprising drug is a selective COX-2 inhibitory drug of low water solubility.
  • Suitable selective COX-2 inhibitory drugs are compounds having the formula (VIII):
  • A is a substituent selected from partially unsaturated or unsaturated heterocyclic and partially unsaturated or unsaturated carbocyclic rings, preferably a heterocyclic group selected from pyrazolyl, furanoyl, isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl groups;
  • X is O, S or CH 2 ; n is O or 1; R is at least one subsituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsufinyl, halo, alkoxy and alkylthio; R 2 is NH 2 group; R 3 is one or more radicals selected from hydrido, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkyltliio, alkylcarbonyl
  • Particularly suitable selective COX-2 inhibitory drugs are compounds having the formula (IX):
  • R 4 is hydrogen or a C M alkyl or alkoxy group
  • X is N or CR 5 where R 5 is hydrogen or halogen
  • Y and Z are independently carbon or nitrogen atoms defining adjacent atoms of a five-to-six-membered ring that is unsubstitated or substituted at one or more positions with oxo, halo, methyl, or halomethyl groups.
  • Preferred such five-to six-membered rings are cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted at no more than one position.
  • compositions ofthe invention are suitable for celecoxib, deracoxib, valdecoxib and JTE-522, more particularly celecoxib, paracoxib and valdecoxib.
  • suitable compositions include Acetazolamide CAS Registry Number: 59-66-5, Acetohexamide CAS Registry Number: 968-81-0, Alpiropride CAS Registry Number: 81982-32-3, Althiazide CAS Registry Number: 5588-16-9, Ambuside CAS Registry Number: 3754-19-6,Amidephrine CAS Registry Number: 3354-67-4, Amosulalol CAS Registry Number: 85320-68-9, Amsacrine CAS Registry Number: 51264-14-3, Argatroban CAS Registry Number: 74863-84-6,
  • Azosemide CAS Registry Number: 27589-33-9 Bendroflumethiazide CAS Registry Number: 73-48-3, Benzthiazide CAS Registry Number: 91-33-8, Benzylhydrochlorothiazide CAS Registry Number: 1824-50-6, p- (Benzylsulfonamido)benzoic Acid CAS Registry Number: 536-95-8, Bosentan CAS Registry Number: 147536-97-8, Brinzolamide CAS Registry Number: 138890- 62-7
  • the pharmaceutical compositions ofthe present invention comprise a salt of celecoxib or valdecoxib, (e.g., sodium, lithium, potassium, magnesium, or calcium salt).
  • the salt may be significantly more soluble in water than the free acid form ofthe API. Due to the high pE ⁇ s of celecoxib and underivatized valdecoxib(approximately 11), salts only form under strongly basic conditions. Typically, more than about one equivalent of a base is required to convert celecoxib and valdecoxib totheir respective salt forms.
  • a suitable aqueous solution for converting either free acid to a salt has a pH of about 11.0 or greater, about 11.5 or greater, about 12 or greater, or about 13 or greater.
  • the pH of such a solution is about 12 to about 13.
  • the invention includes other pharmaceutical drugs with pKaS greater than 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, or 13.
  • the drugs may normally be in a neutral form or a salt form may already exist.
  • Salts ofthe pharmaceutical are formed by reaction ofthe pharmaceutical with an acceptable base.
  • Acceptable bases include, but are not limited to, metal hydroxides and alkoxides.
  • Metals include alkali metals (sodium, potassium, lithium, cesium), alkaline earth metals (magnesium, calcium), zinc, aluminum, and bismuth.
  • Alkoxides include methoxide, ethoxide, n-propoxide, isopropoxide and t-butoxide.
  • Additional bases include arginine, procaine, and other molecules having amino or guanidinium moieties with sufficiently highpK a 's (e.g., pK a 's greater than about 11, pK a 's greater than about 11.5, or pK a 's greater than about 12), along with compounds having a carbon-alkali metal bond (e.g., t-butyl lithium).
  • Sodium hydroxide and sodium ethoxide are preferred bases.
  • the amount of base used to form a salt is typically about one or more, about two or more, about three or more, about four or more, about five or more, or about ten or more equivalents relative to the pharmaceutical.
  • about three to about five equivalents of one or more bases are reacted with the pharmaceutical to form a salt.
  • a pharmaceutical salt can be transformed into a second pharmaceutical salt by transmetallation or another process that replaces the cation ofthe first pharmaceutical salt.
  • a sodium salt ofthe pharmaceutical is prepared and is subsequently reacted with a second salt such as an alkaline earth metal halide (e.g., MgBr 2 , MgCl 2 , CaCl 2 , CaBr 2 ), an alkaline earth metal sulfate or nitrate (e.g.,
  • an alkaline metal salt of an organic acid e.g. calcium formate, magnesium formate, calcium acetate, magnesium acetate, calcium propionate, magnesium propionate
  • an organic acid e.g. calcium formate, magnesium formate, calcium acetate, magnesium acetate, calcium propionate, magnesium propionate
  • the pharmaceutical salts are substantially pure.
  • a salt that is substantially pure can be greater than about 80% pure, greater than about 85% pure, greater than about 90% pure, greater than about 95% pure, greater than about 98%> pure, or greater than about 99% pure.
  • Purity of a salt can be measured with respect to the amount of salt (as opposed to unreacted neutral pharmaceutical or base) or can be measured with respect to a specific polymorph, co- crystal, solvate, desolvate, hydrate, dehydrate, or anhydrous form of a salt.
  • a pharmaceutical salt as described herein may be significantly more soluble in water than the existing neutral form, such as the free acid alone or the presently- marketed neutral celecoxib (CELEBREX), and is typically at least about twice, at least about three times, at least about five times, at least about ten times, at least about twenty times, at least about fifty times, or at least about one hundred times more soluble in water or SGF than the neutral form.
  • CELEBREX is marketed by Pfizer Inc. and G. D. Searle & Co. (Pharmacia Corporation), and described on pages 2676-2680 and 2780-2784 ofthe 2002 edition of he Physicians Desk Reference (also referred to herein as presently-marketed celecoxib).
  • the reference compounds to the present invention herein can refer to the free acid neutral celecoxib, either crystalline or amorphous, CELEBREXTM, the free acid neutral valdecoxib, either crystalline or amorphous, or BEXTRATM.
  • the solubility depends on whether the salt is tested alone, or as a formulation further comprising the precipitation retardants and enhancers ofthe invention.
  • the salt can be neutralized by an acid or by dissolved gases such as carbon dioxide.
  • the pH of such a solution is 11 or less, 10 or less, or 9 or less.
  • Neutralizing the salt results in precipitation of an amorphous or metastable crystalline form of neutral celecoxib.
  • neutralizing a pharmaceutical salt includes protonating the majority of negatively charged anions. For celecoxib, protonation results in the formation of amorphous and/or metastable crystalline celecoxib, which are "neutral" (i.e., predominantly uncharged).
  • the neutral pharmaceutical (including amorphous and/or metastable crystalline forms thereof, such as celecoxib) comprises 10% mol or less of charged molecules.
  • solutions ofthe sodium salt of celecoxib precipitate immediately as an amorphous form of neutral celecoxib.
  • the amorphous form converts to a neutral metastable crystalline form, which subsequently becomes the stable, needle-like, insoluble form of neutral celecoxib.
  • amorphous neutral celecoxib formed from the salts ofthe present invention e.g., the sodium salt of Example 1, converts to metastable crystalline neutral celecoxib over about 5 to about 10 minutes.
  • Amorphous neutral celecoxib can be characterized by a lack of regular crystal structure, while metastable crystalline neutral celecoxib can be distinguished from typical crystalline neutral celecoxib by the PXRD pattern of isolated material.
  • Amorphous and metastable crystalline forms of neutral celecoxib are more soluble and likely more readily absorbed by a subject than stable crystalline forms of neutral celecoxib, because the energy required for a drug molecule to escape from a stable crystal is greater than the energy required for the same drug molecule to escape from a non-crystalline, amorphous form or a metastable crystalline form.
  • the instability of neutral amorphous and neutral metastable crystalline forms makes them difficult to formulate as pharmaceutical compositions. As is described in U.S. Publication No.
  • the drug is solubilized either directly with the precipitation retardant or with a solubilizer or solvent.
  • Preferred solubilizers are polyethylene oxides. More preferably, the polyethylene oxide is a surfactant. Preferred ethylene oxides comprise the functional group - (C 2 H 4 O) n - where n > 2.
  • polyethylene oxides are poloxamers having the general formula HO(C 2 H 4 O) a (C 3 H 6 O) b (C 2 H 4 O) a H where a > 2, where a > 3, where a > 2 and b > 30, where a > 2 and b > 4, where a > 2 and b > 50, where a > 2 and b > 60.
  • An aminosulfonyl containing API (celecoxib) was crystallized with molecules comprising at least two oxygen atoms (e.g., ether groups) to examine the physical interactions involved in precipitation retardation by the precipitation retardant.
  • the precipitation retardant compounds preferably surfactants
  • the retardant molecule comprises at least one, preferably two, 10, 25, 40, 50, 60, 80, 100 or more functional interacting groups, wherein a functional interacting group comprises two oxygen atoms, with each ofthe two oxygen atoms interacting (e.g., hydrogen bonding) with the API.
  • a functional interacting group comprises two oxygen atoms, with each ofthe two oxygen atoms interacting (e.g., hydrogen bonding) with the API.
  • the two oxygen atoms interact with the aminosulfonyl group ofthe API.
  • the aminosulfonyl group is -SO 2 NH 2 .
  • the two interacting oxygen atoms are preferably separated by between about 3.6 angstroms to about 5.8 angstroms, about 3.9 angstroms to about 5.5 angstroms, 4.3 to about 5.2 angstroms, 4.6 to about 5.0 angstroms, or about 4.7 to about 4.9 angstroms.
  • the two oxygen atoms are separated by at least three atoms.
  • the two oxygen atoms are separated by 5 atoms.
  • the two oxygen atoms are separated by 4 carbons and one oxygen atom.
  • the order ofthe 5 atoms is -C-C-O-C-C-, whereby a single unit of he functional interacting group (including the two interacting oxygen atoms), is -O- C-C-O-C-C-O-.
  • Glycol ethers can also be used as solubilizers of neutral or other forms of celecoxib including those that conform with the formula (X):
  • R 1 and R 2 are independently hydrogen or C 1-6 alkyl, C 1-6 alkenyl, phenyl or benzyl groups, but no more than one of R 1 and R 2 is hydrogen; m is an integer of 2 to about 5; and n is an integer of 1 to about 20. It is preferred that one of R 1 and R 2 is a C ⁇ alkyl group and the other is hydrogen or a C alkyl group; more
  • Non-surfactant glycol ethers or more specifically glycol ethers of formula (X) and above, can also be specifically excluded from the present invention.
  • the glycol ethers are surfactants.
  • Compositions ofthe present invention optionally comprise one or more pharmaceutically acceptable co-solvents.
  • Non-limiting examples of co-solvents suitable for use in compositions ofthe present invention include any glycol ether listed above; alcohols, for example ethanol and n-butanol; glycols not listed above; for example propylene glycol, 1,3-butanediol and polyethylene glycol such as PEG-400; oleic and linoleic acid triglycerides, for example soybean oil; caprylic/capric triglycerides, for example MiglyolTM 812 of Huls; caprylic/capric mono- and diglycerides, for example CapmulTM MCM of Abitec; polyoxyethylene caprylic/capric glycerides such as polyoxyethylene caprylic/capric mono- and diglycerides, for example LabrasolTM of Gattefosse; propylene glycol fatty acid esters, for example propylene glycol laurate; polyoxyethylene castor oil, for example CremophorTM EL of BASF; polyoxyethylene glyce
  • Celecoxib salts are preferred because they are stable, such that they can be formulated as pharmaceutical compositions and stored before administration to a subject. Only after dissolution and subsequent neutralization do the celecoxib salts precipitate as or transform into substantially amorphous neutral and then substantially metastable crystalline neutral forms. Preferably, dissolution and neutralization of celecoxib salts occur in situ in the gastrointestinal tract of a subject (e.g., stomach, duodenum, ileum), such that a maximal amount of amorphous and/or metastable crystalline neutral celecoxib is present after administration (e.g., in vivo), rather than before administration.
  • a subject e.g., stomach, duodenum, ileum
  • Underivatized valdecoxib refers to valdecoxib that has not been covalently modified, such as by acylating the sulfonamide moiety (e.g., to form a valdecoxib prodrug). Underivatized valdecoxib can be in the form of either neutral valdecoxib or a salt of valdecoxib.
  • valdecoxib has several advantages over salts of derivatized valdecoxib (e.g., parecoxib, sodium N-acetyl valdecoxib).
  • derivatization of valdecoxib requires an additional synthetic step, requiring the use of additional amounts of organic solvents, which have a high disposal cost.
  • derivatized forms of valdecoxib are typically prodrugs. Prodrugs must be converted, typically in vivo, back to the pharmaceutically active form ofthe drug. As it is desirable for valdecoxib to have a more rapid onset to therapeutic effect, the requirement that a prodrug convert to an active drug potentially delays the therapeutic effect ofthe drug.
  • Dissolution Modulation :
  • the dissolution profile of the API is modulated whereby the aqueous dissolution rate or the dissolution rate in simulated gastric fluid or in simulated intestinal fluid, or in a solvent or plurality of solvents is increased.
  • Dissolution rate is the rate at which API solids dissolve in a dissolution medium.
  • the rate-limiting step in the absorption process is dissolution. Because of a limited residence time at the absorption site, APIs that are not dissolved before they are removed from the intestinal absorption site are considered useless. Therefore, the rate of dissolution has a major impact on the performance of APIs that are poorly soluble.
  • Dissolution rate K S (C 3 -C) where K is the dissolution rate constant, S is the surface area, C s is the apparent solubility (saturated concentration), and C is the concentration of API in the dissolution media.
  • C 3 -C is approximately equal to C s .
  • the dissolution rate of APIs may be measured by conventional means known in the art.
  • the increase in the dissolution rate of a composition ofthe present invention, as compared to the neutral free form, may be specified, such as by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or by 2, 3, 4, 5 ,6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 fold greater than the free form in the same solution. Conditions under which the dissolution rate is measured are discussed above.
  • the increase in dissolution may be further specified by the time the composition remains supersaturated.
  • compositions with a dissolution rate, at 37 degrees C and a pH of 7.0, that is increased at least 5 fold over the neutral free form compositions with a dissolution rate in SGF that is increased at least 5 fold over the neutral free form
  • compositions with a dissolution rate in SIF that is increased at least 5 fold over the neutral free form.
  • the present invention demonstrates that the length of time in which celecoxib, valdecoxib, or other APIs remain in solution can be increased to a surprising high degree by using a salt or co-crystal form with the presence of a precipitation retardant, normally a surfactant (e.g., poloxamer, TPGS, SDS, etc.) and an optional enhancer (e.g., hydroxypropyl cellulose) as discussed herein.
  • a precipitation retardant normally a surfactant (e.g., poloxamer, TPGS, SDS, etc.) and an optional enhancer (e.g., hydroxypropyl cellulose) as discussed herein.
  • a surfactant e.g., poloxamer, TPGS, SDS, etc.
  • an optional enhancer e.g., hydroxypropyl cellulose
  • Neutral free celecoxib for example, has a solubility in water of less than 1 microgram/mL and cannot be maintained as a supersatarated solution for any appreciable time.
  • compositions that can be maintained for a period of time (e.g., 15, 30, 45, 60 minutes and longer) as supersaturated solutions at concentrations 2, 3, 5, 7, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% greater, or solubilities increased by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 fold over the neutral free form in the same solution (e.g., water or SGF).
  • a period of time e.g., 15, 30, 45, 60 minutes and longer
  • the amount of precipitation inhibitor or enhancer may each or together be less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, or 90 %w/w ofthe formulated pharmaceutical(.
  • the %>w/w for either or both precipitation inhibitor and enhancer may also be in a range represented by any two integers of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, or 90.
  • Celecoxib salts ofthe present invention are typically stable (i.e., more than 90% ofthe celecoxib salt does not change in composition or crystalline structure) for at least about one week, at least about one month, at least about two months, at least about three months, at least about six months, at least about nine months, at least about one year, or at least about two years at room temperature in the absence of moisture.
  • Room temperature typically ranges from about 15 degrees C to about 30 degrees C.
  • the absence of moisture, as defined herein, refers to celecoxib salts not contacting quantities of liquid, particularly water or alcohols.
  • gases such as water vapor are not considered to be moisture.
  • compositions ofthe present invention including the active pharmaceutical ingredient (API) and formulations comprising the API, are suitably stable for pharmaceutical use.
  • the API or formulations thereof of the present invention are stable such that when stored at 30 degrees C for 2 years, less than 0.2% of any one degradant is formed.
  • degradant refers herein to product(s) of a single type of chemical reaction. For example, if a hydrolysis event occurs that cleaves a molecule into two products, for the purpose ofthe present invention, it would be considered a single degradant. More preferably, when stored at 40 degrees C for 2 years, less than 0.2% of any one degradant is formed.
  • the relative humidity (RH) may be specified as ambient (RH), 75% (RH), or as any single integer between 1 to 99% (RH).
  • the methods ofthe present invention are used to make a pharmaceutical API formulation with greater solubility, dissolution, bioavailability, AUC, reduced time to Tma x , the average time from administration to reach peak blood serum levels, higher C max> , the average maximum blood serum concentration of API following administration, and longer T 2 , the average terminal half-life of API blood serum concentration following T max , when compared to the neutral free form.
  • AUC is the area under the curve of plasma concentration of API (not logarithm of the concentration) against time after API administration.
  • the area is conveniently determined by the "trapezoidal rule": The data points are connected by straight line segments, perpendiculars are erected from the abscissa to each data point, and the sum of the areas of the triangles and trapezoids so constructed is computed.
  • the AUC from thyroid to infinite time is estimated by Cn/kei-
  • the AUC is of particular use in estimating bioavailability of APIs, and in estimating total clearance of APIs (Cl ⁇ ).
  • AUC F • D/C1 T , where F is the absolute bioavailability ofthe API.
  • the present invention provides a process for modulating the bioavailability of an API when administered in its normal and effective dose range, whereby the AUC is increased, the time to T max is reduced, or C max is increased, which process comprises:
  • compositions with a time to T max that is reduced by at least 10% as compared to the neutral free form compositions with a time to T max that is reduced by at least 20% over the free form, compositions with a time to T max that is reduced by at least 40% over the free form, compositions with a time to T max that is reduced by at least 50% over the free form, compositions with a
  • compositions with a more rapid onset to therapeutic effect typically reach a higher maximum blood serum concentration (C max ) a shorter time after oral administration (T max )-
  • compositions, preferably including salts, ofthe present invention have a higher C ma ⁇ and/or a shorter T m a x than presently-marketed celecoxib.
  • the T max for the compositions of the present invention occurs within about 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, or within about 5 minutes of administration (e.g., oral administration).
  • compositions of the present invention begin to occur within about 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, within about 25 minutes, within about 20 minutes, within about 15 minutes, within about 10 minutes, or within about 5 minutes of administration (e.g., oral administration).
  • Karim et al. report about a 2.5-fold increase in C max over that of presently- marketed celecoxib (CELEBREX) by the suspension of neutral free form celecoxib particles in an aqueous liquid.
  • the present invention produces an increase in C ma ⁇ of about four-fold over that ofthe presently-marketed drug.
  • the present invention yields an increase in the AUC of at least about two-fold over that of presently-marketed celecoxib.
  • Compositions of the present invention have a bioavailability greater than neutral celecoxib and currently-marketed CELEBREX.
  • the compositions ofthe present invention have a bioavailability of at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% greater than that of neutral celecoxib and currently-marketed CELEBREX.
  • Administration of the present invention to a subject may result in effective pain relief.
  • the desired therapeutic effect calls for r ⁇ ter alia an appropriate blood serum concentration ofthe API.
  • Effective blood serum concentrations of celecoxib can range based on many factors (e.g., age, weight, etc.) but generally are about 10 ng/mL to about 500 ng/mL, or about 25 ng/mL to 400 ng/mL, or about 50 ng/mL to about 300 ng/mL. Specifically, about 250 ng/mL is often suitable for effective pain relief.
  • an effective dosage of celecoxib will be found in the range of about 1 mg/kg to about 6 mg/kg body weight. For an average 75 kg subject, this range equates to a celecoxib dose of about 75 mg to about 450 mg.
  • an "effective pain-relieving concentration” or “effective pain-relieving blood serum concentration” as used herein is intended to mean a blood serum level in a patient which when tested in a standardized test involving patient scoring ofthe severity of pain, achieves a mean score indicating pain relief.
  • patients score pain on a scale of from 0 (no reduction in severity of pain) to 4 (complete relief of pain) and a mean score equal to or greater than a given value is deemed to constitute effective pain-relief.
  • a mean score of 0.5 or greater and, more preferably, 1.0 or greater in such a test, as exemplified herein, is deemed to constitute effective pain relief.
  • the skilled artisan will appreciate, however, that other approaches can be used to assess the severity of pain and relief from such pain.
  • one aspect ofthe present invention involves a therapeutic method for analgesia in which a composition comprising a celecoxib salt or co-crystal, or a valdecoxib salt or co-crystal is administered orally to a subject, in a formulation that provides detectable pain relief not later than about 30 minutes after oral administration.
  • detectable pain relief it is meant that the formulation produces effective pain relief that is measurable by a standard method such as that described above.
  • a formulation which achieves a mean score of 0.5 or greater and, more preferably, 1.0 or greater on a scale of from 0 to 4 in a testing system as described above, is deemed to provide detectable pain relief.
  • the invention is not limited to use of any particular type of formulation, so long as it exhibits the pharmacokinetic profile defined herein.
  • suitable formulation types are described below. Protocols for conducting human pharmacokinetic studies are well known in the art and any standard protocol can be used to determine whether a particular formulation satisfies the pharmacokinetic criteria set out herein. An example of a suitable protocol is described below.
  • An advantage ofthe present invention is that relief of pain, even intense pain as can occur, for example, following oral, general or orthopedic surgery, is achieved significantly faster, i.e., in a significantly shorter time after administration, than is achievable with standard formulations of celecoxib.
  • Any standard pharmacokinetic protocol can be used to determine blood serum concentration profile in humans following oral administration of a celecoxib formulation, and thereby establish whether that formulation meets the pharmacokinetic criteria set out herein.
  • a randomized single-dose crossover study can be performed using a group of healthy adult human subjects.
  • the number of subjects is sufficient to provide adequate control of variation in a statistical analysis, and is typically about 10 or greater, although for certain pu ⁇ oses a smaller group can suffice.
  • Each subject receives, by oral administration at time zero, a single dose (e.g., 200 mg) of a test formulation of celecoxib, normally at around 8 am following an overnight fast. The subject continues to fast and remains in an upright position for about 4 hours after administration ofthe celecoxib formulation. Blood samples are collected from each subject before administration (e.g., 15 minutes prior to administration) and at several intervals after administration.
  • blood samples can be collected 15, 30, 45, 60 and 90 minutes after administration, then every hour from 2 to 10 hours after administration.
  • additional blood samples can be taken later, for example 12 and 24 hours after administration.
  • Plasma is separated from the blood samples by centrifugation and the separated plasma is analyzed for celecoxib by a validated high performance liquid chromatography (HPLC) procedure with a lower limit of detection of 10 ng/mL (see for example, Paulson et al., Drug Metab. Dispos.
  • HPLC high performance liquid chromatography
  • Blood serum concentrations of celecoxib referenced herein are intended to mean total celecoxib concentrations including both free and bound celecoxib as determined upon extraction from the plasma sample and HPLC detection according to methods known in the art such as those identified above.
  • the present invention provides a process for improving the dose response of an API by making a composition of the present invention.
  • Dose response is the quantitative relationship between the magnitude of response and the dose inducing the response and may be measured by conventional means known in the art.
  • the curve relating effect (dependent variable) to dose (independent variable) for an API-cell system is the "dose-response curve".
  • dose-response curve is the measured response to an API plotted against the dose of the API (mg/kg) given.
  • the dose response curve can also be a curve of AUC against the dose ofthe API given.
  • the dose-response curve for presently-marketed celecoxib is nonlinear.
  • the dose-response curve for celecoxib salt and co-crystal compositions of the present invention is linear or contains a larger linear region than presently-marketed celecoxib.
  • the abso ⁇ tion or uptake of presently-marketed celecoxib depends in part on food effects, such that uptake of celecoxib increases when taken with food, especially fatty food.
  • uptake of celecoxib salts ofthe present invention exhibits a decreased dependence on food, such that the difference in uptake of celecoxib salts when taken with food and when not taken with food is less than the difference in uptake of presently-marketed celecoxib.
  • the present invention provides for APIs with decreased hygroscopicity and a method for decreasing the hygroscopicity of an API by making the same.
  • An aspect of the present invention provides a pharmaceutical composition of an API that is less hygroscopic than amo ⁇ hous or crystalline free form.
  • Hygroscopicity can be assessed by dynamic vapor so ⁇ tion analysis, in which 5-50 mg of the compound is suspended from a Cahn microbalance.
  • the compound being analyzed should be placed in a non-hygroscopic pan and its weight should be measured relative to an empty pan composed of identical material and having nearly identical size, shape, and weight. Ideally, platinum pans should be used.
  • the pans should be suspended in a chamber through which a gas, such as air or nitrogen, having a controlled and known percent relative humidity (% RH) is flowed until eqilibrium criteria are met.
  • a gas such as air or nitrogen
  • % RH percent relative humidity
  • Typical equilibrium criteria include weight changes of less than 0.01 % change over 3 minutes at constant humidity and temperature.
  • the relative humidity should be measured for samples dried under dry nitrogen to constant weight ( ⁇ 0.01 % change in 3 minutes) at 40 degrees C unless doing so would de-solvate or otherwise convert the material to an amo ⁇ hous compound.
  • the hygroscopicity of a dried compound can be assessed by increasing the RH from 5 to 95 % in increments of 5 % RH and then decreasing the RH from 95 to 5 % in 5 % increments to generate a moisture so ⁇ tion isotherm.
  • the sample weight should be allowed to equilibrate between each change in % RH. If the compound deliquesces or becomes amo ⁇ hous above 75 % RH but below 95 % RH, the experiment should be repeated with a fresh sample and the relative humidity range for the cycling should be narrowed to 5-75 % RH or 10-75 % RH instead of 5-95 %> RH.
  • the sample cannot be dried prior to testing due to lack of form stability, than the sample should be studied using two complete humidity cycles of either 10-75 % RH or 5-95 % RH, and the results ofthe second cycle should be used if there is significant weight loss at the end ofthe first cycle.
  • Hygroscopicity can be defined using various parameters.
  • a non-hygroscopic molecule should not gain or lose more than 1.0 %, or more preferably, 0.5 % weight at 25 degrees C when cycled between 10 and 75 % RH (relative humidity at 25 degrees C).
  • the non-hygroscopic molecule more preferably should not gain or lose more than 1.0%, or more preferably, 0.5 % weight when cycled between 5 and 95 %RH at 25 degrees C, or 0.25 %> of its weight between 10 and 75 % RH.
  • a non-hygroscopic molecule will not gain or lose more than 0.25 % of its weight when cycled between 5 and 95 % RH.
  • hygroscopicity can be defined using the parameters of Callaghan et al., Equilibrium Moisture Content of Pharmaceutical Excipients, in API Dev. Ind. Pharm., Vol. 8, pp. 335-369 (1982). Callaghan et al. classified the degree of hygroscopicity into four classes.
  • Class 1 Non-hygroscopic Essentially no moistare increases occur at relative humidities below 90 %.
  • Class 2 Slightly hygroscopic Essentially no moisture increases occur at relative humidities below 80 %.
  • Class 3 Moderately hygroscopic Moistare content does not increase more than 5 % after storage for 1 week at relative humidities below 60 %.
  • Class 4 Very hygroscopic Moisture content increase may occur at relative humidities as low as 40 to 50 %.
  • hygroscopicity can be defined using the parameters ofthe European Pharmacopoeia Technical Guide (1999, p. 86) which has defined hygroscopicity, based on the static method, after storage at 25 degrees C for 24 h at 80 % RH:
  • Hygroscopic Increase in mass is less than 15 % m/m and equal to or greater than 0.2 % m/m.
  • Deliquescent Sufficient water is absorbed to form a liquid.
  • compositions ofthe present invention can be set forth as being in Class 1, Class 2, or Class 3, or as being Slightly hygroscopic, Hygroscopic, or Very Hygroscopic. Compositions ofthe present invention can also be set forth based on their ability to reduce hygroscopicity. Thus, preferred compositions ofthe present invention are less hygroscopic than the neutral free form. Further included in the present invention are compositions that do not gain or lose more than 1.0 %> weight at 25 degrees C when cycled between 10 and 75 % RH, wherein the reference compound gains or loses more than 1.0 % weight under the same conditions.
  • compositions that do not gain or lose more than 0.5 % weight at 25 degrees C when cycled between 10 and 75 % RH, wherein the reference compound gains or loses more than 0.5 % or more than 1.0 % weight under the same conditions. Further included in the present invention are compositions that do not gain or lose more than 1.0 % weight at 25 degrees C when cycled between 5 and 95 % RH, wherein the reference compound gains or loses more than 1.0 % weight under the same conditions. Further included in the present invention are compositions that do not gain or lose more than 0.5% weight at 25 degrees C when cycled between 5 and 95 % RH, wherein the reference compound gains or loses more than 0.5 % or more than 1.0 % weight under the same conditions.
  • compositions that do not gain or lose more than 0.25 %> weight at 25 degrees C when cycled between 5 and 95 % RH, wherein the reference compound gains or loses more than 0.5 % or more than 1.0 % weight under the same conditions.
  • compositions that have a hygroscopicity (according to Callaghan et al.) that is at least one class lower than the reference compound or at least two classes lower than the reference compound.
  • Class 1 composition of a Class 2 reference compound a Class 1 composition of a Class 2 reference compound
  • Class 2 composition of a Class 3 reference compound a Class 3 composition of a Class 4 reference compound
  • Class 1 composition of a Class 3 reference compound a Class 1 composition of a Class 4 reference compound
  • Class 2 composition of a Class 4 reference compound or a Class 2 composition of a Class 4 reference compound.
  • compositions that have a hygroscopicity (according to the European Pharmacopoeia Technical Guide) that is at least one class lower than the reference compound or at least two classes lower than the reference compound.
  • Non-limiting examples include a Slightly hygroscopic composition of a Hygroscopic reference compound, a Hygroscopic composition of a Very Hygroscopic reference compound, a Very Hygroscopic composition of a Deliquescent reference compound, a Slightly hygroscopic composition of a Very Hygroscopic reference compound, a Slightly hygroscopic composition of a Deliquescent reference compound, a Hygroscopic composition of a Deliquescent reference compound.
  • Celecoxib salts can be characterized by differential scanning calorimetry (DSC).
  • the sodium salt of celecoxib prepared in Example 1 is characterized by at least 3 overlapping endothermic transitions between 50 degrees C and 110 degrees C (Fig. 1). Conditions for DSC can be found in Example 1.
  • Celecoxib salts can be characterized by thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • the sodium salt product prepared by Example 1 was characterized by TGA, and was determined to have about 3 loosely bound equivalents of water that evaporated between about 30 degrees C and about 40 degrees C, one more tightly bound equivalent of water that evaporated between about 40 degrees C and about 100 degrees C, and one very tightly bound equivalent of water that evaporated between about 140 degrees C and about 160 degrees C (Fig. 2).
  • the sodium salt can exist at different states of hydration depending on the humidity, temperature, and other conditions. Conditions for TGA can be found in the Exemplification section.
  • Celecoxib salts ofthe present invention can also be characterized by powder X- ray diffraction (PXRD).
  • the sodium salt of celecoxib prepared by Example 1 had an intense reflection or peak at a 2-theta angle of 6.36 degrees, and other reflections or peaks at 7.01 , 18.72, and 20.83 degrees (Fig. 3).
  • Conditions for PXRD can be found in Example 1.
  • Celecoxib salts may comprise solvate molecules and can occur in a variety of solvation states, also known as solvates.
  • celecoxib salts can exist as crystalline polymo ⁇ hs.
  • Polymo ⁇ hs are different crystalline forms ofthe same drug substance, and in the present use ofthe term include solvates and hydrates.
  • different polymo ⁇ hs of a celecoxib salt can be obtained by varying the method of preparation (compare Examples). Crystalline polymo ⁇ hs typically have different solubilities, such that a more thermodynamically stable polymo ⁇ h is less soluble than a less thermodynamically stable polymo ⁇ h.
  • Suitable solvate molecules include water, alcohols, other polar organic solvents, and combinations thereof. Alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, propylene glycol and t-butanol. Propylene glycol solvates are particularly preferred because they are more stable and less hygroscopic than other forms. Alcohols also include polymerized alcohols such as polyalkylene glycols (e.g., polyethylene glycol, polypropylene glycol). In an embodiment, water is the solvent.
  • a celecoxib salt contains about 0.0 %, less than 0.5 %, 0.5, less than 1.0 %, 1.0, less than 1.5 %, 1.5, less than 2.0 %, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 or about 6.0 equivalents, or about 1.0 to about 6.0, 2.0 to about 5.0, 3.0 to about 6.0, 3.0 to about 5.0, 1.0 to about 4.0, 2.0 to about 4.0, 1.0 to about 3.0, 2.0 to about 3.0, 0.0 to about 3.0, 0.5 to about 3.0, 0.0 to about 2.0, 0.5 to about 2.0, 0.0 to about 1.5, 0.5 to about 1.5, 1.0 to about 1.5, or 0.5 to about 1.0 equivalents of water per equivalent of salt.
  • Solvate molecules can be removed from a crystalline salt, such that the salt is either a partial or complete desolvate. If the solvate molecule is water (forming a hydrate), then a desolvated salt is said to be a dehydrate. A salt with all water removed is anhydrous. Solvate molecules can be removed from a salt by methods such as heating, treating under vacuum or reduced pressure, blowing dry air over a salt, or a combination thereof. Following desolvation, there are typically about one to about five equivalents, about one to about four equivalents, about one to about three equivalents, or about one to about two equivalents of solvent per equivalent of salt in a crystal.
  • co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion. Solvates of API compounds that do not further comprise a co-crystal forming compound are not co-crystals according to the present invention.
  • the co-crystals may however, include one or more solvent molecules in the crystalline lattice.
  • solvates of co-crystals or a co-crystal further comprising a solvent or compound that is a liquid at room temperature, is included in the present invention, but crystalline material comprised of only one solid and one or more liquids (at room temperature) are not included by the term "co-crystal".
  • the co-crystals may include a co-crystal former and a salt of an API, but the API and the co-crystal former ofthe present invention are constructed or bonded together through hydrogen bonds.
  • Other modes of molecular recognition may also be present including, ⁇ -stacking, guest-host complexation and van der Waals interactions.
  • the co-crystal former is a second API.
  • the co-crystal former is not an API.
  • the composition is a co- crystal.
  • the co-crystal formers are selected from one or two (for ternary co-crystals) ofthe following: saccharin, nicotinamide, pyridoxine (4-pyridoxic acid), acesulfame, glycine, arginine, asparagine, cysteine, glutamine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, threonine, tyrosine, valine, aspartic acid, glutamic acid, tryptophan, adenine, acetohydroxamic acid, alanine, allopurinaol, 4-aminobenzoic acid, cyclamic acid, 4-ethoxyphenyl urea, 4- aminopyridine, leucine, nicotinic acid, serine, tris, vitamin k5, xylito, succinic acid, tartaric acid, pyridoxamine, ascorbic acid
  • Celecoxib salts may be prepared by contacting celecoxib with a solvent.
  • Suitable solvents include water, alcohols, other polar organic solvents, and combinations thereof. Water and isopropanol are preferred solvents.
  • Celecoxib is reacted with a base, where suitable bases are listed above, such that celecoxib forms a salt and preferably dissolves.
  • Bases can be added to celecoxib with the solvent (i.e., dissolved in the solvent), such that celecoxib is solvated and deprotonated essentially simultaneously, or bases can be added after the celecoxib has been contacted with solvent (e.g., see Examples).
  • bases can either be dissolved in a solvent, which can be either the solvent already contacting celecoxib or a different solvent, can be added as a neat solid or liquid, or a combination thereof.
  • a solvent which can be either the solvent already contacting celecoxib or a different solvent
  • bases can be added as a neat solid or liquid, or a combination thereof.
  • Sodium hydroxide and sodium ethoxide are preferred bases.
  • the amount of base required is discussed above.
  • the solvent can be evaporated to obtain crystals ofthe celecoxib salt, or the celecoxib salt may precipitate and/or crystallize independent of evaporation. Crystals of a celecoxib salt can be filtered to remove bulk solvent. Methods of removing solvated solvent molecules are discussed above.
  • Excipients employed in pharmaceutical compositions of the present invention can be solids, semi-solids, liquids or combinations thereof. Preferably, excipients are solids.
  • compositions ofthe invention containing excipients can be prepared by any known technique of pharmacy that comprises admixing an excipient with a drug or therapeutic agent.
  • a pharmaceutical composition ofthe invention contains a desired amount of celecoxib per dose unit and, if intended for oral administration, can be in the form, for example, of a tablet, a caplet, a pill, a hard or soft capsule, a lozenge, a cachet, a dispensable powder, granules, a suspension, an elixir, a dispersion, a liquid, or any other form reasonably adapted for such administration.
  • parenteral administration it can be in the form, for example, of a suspension or transdermal patch.
  • If intended for rectal administration it can be in the form, for example, of a suppository.
  • oral dosage forms that are discrete dose units each containing a predetermined amount ofthe drug, such as tablets or capsules.
  • compositions ofthe invention optionally comprise one or more pharmaceutically acceptable carriers or diluents as excipients.
  • suitable carriers or diluents illustratively include, but are not limited to, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., CelutabTM and Emdex ); mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amy
  • Such carriers or diluents constitute in total about 5 % to about 99 %, preferably about 10 % to about 85 %, and more preferably about 20 % to about 80 %, ofthe total weight ofthe composition.
  • the carrier, carriers, diluent, or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.
  • Lactose, mannitol, dibasic sodium phosphate, and microcrystalline cellulose are preferred diluents. These diluents are chemically compatible with celecoxib.
  • the use of extragranular microcrystalline cellulose that is, microcrystalline cellulose added to a granulated composition) can be used to improve hardness (for tablets) and/or disintegration time.
  • Lactose, especially lactose monohydrate is particularly preferred. Lactose typically provides compositions having suitable release rates of celecoxib, stability, pre-compression flowability, and/or drying properties at a relatively low diluent cost.
  • compositions ofthe invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, particularly for tablet formulations.
  • suitable disintegrants include, but are not limited to, either individually or in combination, starches, including sodium starch glycolate (e.g., ExplotabTM of PenWest) and pregelatinized corn starches (e.g., NationalTM 1551 of National Starch and Chemical Company, National 1550, and Colocorn 1500), clays (e.g., VeegumTM HV of R.T.
  • Vanderbilt celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-SolTM of FMC), alginates, crospovidone, and gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums.
  • Disintegrants may be added at any suitable step during the preparation ofthe composition, particularly prior to granulation or during a lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2 % to about 30 %, preferably about 0.2 % to about 10 %, and more preferably about 0.2 % to about 5 %, ofthe total weight ofthe composition.
  • Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, and, if present, preferably constitutes about 0.2 % to about 10 %, more preferably about 0.2 % to about 7 %, and still more preferably about 0.2 % to about 5 %, ofthe total weight ofthe composition. Croscarmellose sodium confers superior intragranular disintegration capabilities to granulated pharmaceutical compositions of the present invention.
  • compositions ofthe invention optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients, particularly for tablet formulations.
  • binding agents and adhesives preferably impart sufficient cohesion to the powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion.
  • binding agents may also further prevent or inhibit crystallization or recrystallization/precipitation of a celecoxib salt ofthe present invention once the salt has been dissolved in a solution.
  • Suitable binding agents and adhesives include, but are not limited to, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g., NationalTM 1511 and NationalTM 1500); celluloses such as, but not limited to, methylcellulose and carmellose sodium (e.g., TyloseTM); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites; povidone, for example povidone K-15, K- 30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (e.g., KlucelTM of Aqualon); and ethylcellulose (e.g., EthocelTM ofthe Dow Chemical Company).
  • Such binding agents and/or adhesives if present, constitute in total about 0.5 % to about 25 %, preferably about 0.75 % to about 15 %
  • binding agents are polymers comprising amide, ester, ether, alcohol or ketone groups and, as such, are preferably included in pharmaceutical compositions ofthe present invention.
  • Polyvinylpynolidones such as povidone K-30 are especially preferred.
  • Polymeric binding agents can have varying molecular weight, degrees of crosslinking, and grades of polymer.
  • Polymeric binding agents can also be copolymers, such as block co-polymers that contain mixtures of ethylene oxide and propylene oxide units. Variation in these units' ratios in a given polymer affects properties and performance. Examples of block co-polymers with varying compositions of block units are Poloxamer 188 and Poloxamer 237 (BASF Co ⁇ oration).
  • compositions ofthe invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients.
  • Such wetting agents are preferably selected to maintain the celecoxib in close association with water,, a condition that is believed to improve bioavailability ofthe composition.
  • Such wetting agents can also be useful in solubilizing or increasing the solubility of metal salts of celecoxib.
  • Non-limiting examples of surfactants that can be used as wetting agents (not necessarily as the precipitation retardant) in pharmaceutical compositions ofthe invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example poly
  • Wetting agents that are anionic surfactants are prefened.
  • Sodium lauryl sulfate is a particularly prefened wetting agent.
  • Sodium lauryl sulfate, if present, constitutes about 0.25 % to about 7 %, more preferably about 0.4 % to about 4 %, and still more preferably about 0.5 % to about 2 %, ofthe total weight ofthe pharmaceutical composition.
  • compositions ofthe invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or glidants) as excipients.
  • suitable lubricants include, but are not limited to, either individually or in combination, glyceryl behapate (e.g., CompritolTM 888 of Gattefosse); stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils (e.g., SterotexTM of Abitec); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., CarbowaxTM 4000 and CarbowaxTM 6000 ofthe Dow Chemical Company); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate.
  • glyceryl behapate e.g., CompritolTM 888 of
  • Such lubricants if present, constitute in total about 0. 1 % to about 10 %, preferably about 0.2 % to about 8 %, and more preferably about 0.25 %> to about 5 %, ofthe total weight ofthe pharmaceutical composition.
  • Magnesium stearate is a prefened lubricant used, for example, to reduce friction between the equipment and granulated mixture during compression of tablet formulations.
  • Suitable anti-adherents include, but are not limited to, talc, cornstarch, DL- leucine, sodium lauryl sulfate and metallic stearates.
  • Talc is a prefened anti-adherent or glidant used, for example, to reduce formulation sticking to equipment surfaces and also to reduce static in the blend.
  • Talc if present, constitutes about 0.1 %> to about 10 %, more preferably about 0.25 % to about 5 %, and still more preferably about 0.5 % to about 2 %, ofthe total weight ofthe pharmaceutical composition.
  • Glidants can be used to promote powder flow of a solid formulation. Suitable glidants include, but are not limited to, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal silicon dioxide is particularly prefened. Other excipients such as colorants, flavors and sweeteners are known in the pharmaceutical arts and can be used in pharmaceutical compositions ofthe present invention. Tablets can be coated, for example with an enteric coating, or uncoated. Compositions ofthe invention can further comprise, for example, buffering agents.
  • one or more effervescent agents can be used as disintegrants and/or to enhance organoleptic properties of pharmaceutical compositions ofthe invention.
  • one or more effervescent agents are preferably present in a total amount of about 30 % to about 75 %, and preferably about 45 %> to about 70 %, for example about 60 %, by weight ofthe pharmaceutical composition.
  • an effervescent agent present in a solid dosage form in an amount less than that effective to promote disintegration ofthe dosage form, provides improved dispersion ofthe celecoxib in an aqueous medium.
  • an effervescent agent is effective to accelerate dispersion of celecoxib from the dosage form in the gastrointestinal tract, thereby further enhancing abso ⁇ tion and rapid onset of therapeutic effect.
  • an effervescent agent is preferably present in an amount of about 1 % to about 20 %, more preferably about 2.5 % to about 15 %, and still more preferably about 5 % to about 10 % by weight ofthe pharmaceutical composition.
  • an “effervescent agent” herein is an agent comprising one or more compounds which, acting together or individually, evolve a gas on contact with water.
  • the gas evolved is generally oxygen or, most commonly, carbon dioxide.
  • Prefened effervescent agents comprise an acid and a base that react in the presence of water to generate carbon dioxide gas.
  • the base comprises an alkali metal or alkaline earth metal carbonate or bicarbonate and the acid comprises an aliphatic carboxylic acid.
  • Non-limiting examples of suitable bases as components of effervescent agents useful in the invention include carbonate salts (e.g., calcium carbonate), bicarbonate salts (e.g., sodium bicarbonate), sesquicarbonate salts, and mixtures thereof.
  • carbonate salts e.g., calcium carbonate
  • bicarbonate salts e.g., sodium bicarbonate
  • sesquicarbonate salts e.g., calcium carbonate
  • Calcium carbonate is a prefened base.
  • Non-limiting examples of suitable acids as components of effervescent agents and/or solid organic acids useful in the invention include citric acid, tartaric acid (as D-, L-, or D/L-tartaric acid), malic acid, aleic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides of such acids, acid salts of such acids, and mixtures thereof.
  • Citric acid is a prefened acid.
  • the weight ratio of the acid to the base is about 1 : 100 to about 100:1, more preferably about 1:50 to about 50:1, and still more preferably about 1 : 10 to about 10:1.
  • the ratio ofthe acid to the base is approximately stoichiometric.
  • Excipients which solubilize metal salts of celecoxib typically have both hydrophilic and hydrophobic regions, or are preferably amphiphilic or have amphiphilic regions.
  • amphiphilic or partially-amphiphilic excipient comprises an amphiphilic polymer or is an amphiphilic polymer.
  • a specific amphiphilic polymer is a polyalkylene glycol, which is commonly comprised of ethylene glycol and/or propylene glycol subunits. Such polyalkylene glycols can be esterified at their termini by a carboxylic acid, ester, acid anhyride or other suitable moiety.
  • excipients examples include poloxamers (symmetric block copolymers of ethylene glycol and propylene glycol; e.g., poloxamer 237), polyalkyene glycolated esters of tocopherol (including esters formed from a di- or multi-functional carboxylic acid; e.g., d-alpha-tocopherol polyethylene glycol-1000 succinate), and macrogolglycerides (formed by alcoholysis of an oil and esterification of a polyalkylene glycol to produce a mixture of mono-, di- and tri-glycerides and mono- and di-esters; e.g., stearoyl macrogol-32 glycerides).
  • poloxamers symmetric block copolymers of ethylene glycol and propylene glycol
  • polyalkyene glycolated esters of tocopherol including esters formed from a di- or multi-functional carboxylic acid; e.g., d-alpha-tocopherol
  • compositions ofthe present invention can comprise about 10 % to about 50 %, about 25 % to about 50 %, about 30 % to about 45 %, or about 30 % to about 35 % by weight of a metal salt of celecoxib; about 10 % to about 50 %, about 25 % to about 50 %, about 30 % to about 45 %, or about 30 % to about 35 % by weight of an excipient which inhibits precipitation; and about 5 % to about 50 %, about 10 % to about 40 %, about 15 % to about 35 %, or about 30 % to about 35 % by weight of a binding agent.
  • the weight ratio ofthe metal salt of celecoxib to the excipient which inhibits precipitation to binding agent is about 1 to 1 to 1.
  • the resulting formulations described above are both physically and chemically stable.
  • the present invention can be prepared in solid dosage form well in advance (e.g., months) of oral administration without the risk of premature neutralization or precipitation ofthe API.
  • Liquid suspensions of celecoxib particles can suffer from a tendency ofthe particles to agglomerate and/or increase in size by crystal growth after only several minutes of standing. This crystal growth can significantly reduce the bioavailability and therapeutic effect ofthe drug.
  • Solid dosage forms ofthe invention can be prepared by any suitable process, and are not limited to processes described herein.
  • An illustrative process comprises (i) a step of blending a celecoxib salt ofthe invention with one or more excipients to form a blend, and (ii) a step of tableting or encapsulating the blend to form tablets or capsules, respectively.
  • solid dosage forms are prepared by a process comprising (a) a step of blending the celecoxib salt to form a blend, (b) a step of granulating the blend to form a granulate, and (c) a step of tableting or encapsulating the blend to form tablets or capsules respectively.
  • Step (b) can be accomplished by any dry or wet granulation technique known in the art.
  • a celecoxib salt is advantageously granulated to form particles of about 10 micrometer to about 1000 micrometer, about 25 micrometer to about 500 micrometer, or about 50 micrometer to about 300 micrometer. More specifically, particles of about 100 micrometers in diameter are well suited to yield the desired therapeutic effect.
  • One or more diluents, one or more disintegrants and one or more binding agents may be added, for example in the blending step, a wetting agent can optionally be added, for example in the granulating step, and one or more disintegrants may be added after granulating but before tableting or encapsulating.
  • a lubricant may be added before tableting.
  • Blending and granulating can be performed independently under low or high shear.
  • a process is preferably selected that forms a granulate that is uniform in drug content, that readily disintegrates, that flows with sufficient ease so that weight variation can be reliably controlled during capsule filling or tableting, and that is dense enough in bulk so that a batch can be processed in the selected equipment and individual doses fit into the specified capsules or tablet dies.
  • solid dosage forms are prepared by a process that includes a spray drying step, wherein a celecoxib salt is suspended with one or more excipients in one or more sprayable liquids, preferably a non-protic (e.g., non-aqueous or non-alcoholic) sprayable liquid, and then is rapidly spray dried over a cunent of warm air.
  • a spray drying step wherein a celecoxib salt is suspended with one or more excipients in one or more sprayable liquids, preferably a non-protic (e.g., non-aqueous or non-alcoholic) sprayable liquid, and then is rapidly spray dried over a cunent of warm air.
  • a granulate or spray dried powder resulting from any ofthe above illustrative processes can be compressed or molded to prepare tablets or encapsulated to prepare capsules.
  • Conventional tableting and encapsulation techniques known in the art can be employed. Where coated tablets are desired, conventional coating techniques are suitable.
  • Excipients for tablet compositions ofthe invention are preferably selected to provide a disintegration time of less than about 30 minutes, preferably about 25 minutes or less, more preferably about 20 minutes or less, and still more preferably about 15 minutes or less, in a standard disintegration assay.
  • Celecoxib dosage forms ofthe invention preferably comprise celecoxib in a daily dosage amount of about 10 mg to about 1000 mg, more preferably about 50 mg to about 100 mg, about 100 mg to about 150 mg, 150 mg to about 200 mg, 200 mg to about 250 mg, 250 mg to about 300 mg, 300 mg to about 350 mg, 350 mg to about 400 mg, 400 mg to about 450 mg 450 mg to about 500 mg, 500 mg to about 550 mg, 550 mg to about 600 mg, 600 mg to about 700 mg, and 700 mg to about 800 mg.
  • compositions ofthe invention comprise one or more orally deliverable dose units.
  • Each dose unit comprises celecoxib in a therapeutically effective amount that is preferably those listed.
  • dose unit herein means a portion of a pharmaceutical composition that contains an amount of a therapeutic or prophylactic agent, in the present case celecoxib, suitable for a single oral administration to provide a therapeutic effect.
  • one dose unit, or a small plurality (up to about 4) of dose units, in a single administration provides a dose comprising a sufficient amount ofthe agent to result in the desired effect.
  • Administration of such doses can be repeated as required, typically at a dosage frequency of 1, 2, 3, or 4 times per day.
  • a “subject" to which a celecoxib salt or a pharmaceutical composition thereof can be administered includes a human subject of either sex and of any age, and also includes any nonhuman animal, particularly a warm-blooded animal, more particularly a domestic or companion animal, illustratively a cat, dog or horse.
  • an amount of celecoxib (measured as the neutral form of celecoxib, that is, not including counterions in a salt or water in a hydrate) relatively low in the prefened range of about 10 mg to about 1000 mg is likely to provide blood serum concentrations consistent with therapeutic effectiveness.
  • an amount of celecoxib (measured as the neutral form of celecoxib, that is, not including counterions in a salt or water in a hydrate) relatively low in the prefened range of about 10 mg to about 1000 mg is likely to provide blood serum concentrations consistent with therapeutic effectiveness.
  • achievement of such blood serum concentrations of celecoxib is likely to require dose units containing a relatively greater amount of celecoxib.
  • Typical dose units in a pharmaceutical composition ofthe invention contain about 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 mg of celecoxib.
  • a therapeutically effective amount of celecoxib per dose unit in a composition ofthe present invention is typically about 50 mg to about 400 mg.
  • Especially prefened amounts of celecoxib per dose unit are about 100 mg to about 200 mg, for example about 100 mg or about 200 mg.
  • Other doses that are not in cunent use for CELEBREX may become prefened, if the bioavailability is changed with a novel formulation. For instance, 300 mg may become a prefened dose for certain indications.
  • a dose unit containing a particular amount of celecoxib can be selected to accommodate any desired frequency of administration used to achieve a desired daily dosage.
  • the daily dosage and frequency of administration, and therefore the selection of appropriate dose unit depends on a variety of factors, including the age, weight, sex and medical condition ofthe subject, and the nature and severity ofthe condition or disorder, and thus may vary widely.
  • compositions ofthe present invention can be used to provide a daily dosage of celecoxib of about 50 mg to about 1000 mg, preferably about 100 mg to about 600 mg, more preferably about 150 mg to about 500 mg, and still more preferably about 175 mg to about 400 mg, for example about 200 mg.
  • the daily dose can be administered in one to about four doses per day.
  • oral administration herein includes any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth ofthe subject, whether or not the agent or composition is immediately swallowed, although each are embodiments ofthe invention.
  • oral administration includes buccal and sublingual as well as esophageal administration. Abso ⁇ tion ofthe agent can occur in any part or parts ofthe gastrointestinal tract including the mouth, esophagus, stomach, duodenum, ileum and colon.
  • orally deliverable herein means suitable for oral administration.
  • Pharmaceutically acceptable salts of celecoxib and valdecoxib can be administered by controlled- or delayed-release means.
  • Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counte ⁇ arts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Controlled-release formulations include: 1) extended activity ofthe drug; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total drug; 5) reduction in local or systemic side effects; 6) minimization of drug accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of drug activity; and 10) improvement in speed of confrol of diseases or conditions.
  • Kim Cherng-ju, Controlled Release Dosage Form Design, 2 (Technomic Publishing, Lancaster, Pa.: 2000).
  • Conventional dosage forms generally provide rapid or immediate drug release from the formulation.
  • use of conventional dosage forms can lead to wide fluctuations in the concentrations ofthe drug in a patient's blood and other tissues. These fluctuations can impact a number of parameters, such as dose frequency, onset of action, duration of efficacy, maintenance of therapeutic blood levels, toxicity, side effects, and the like.
  • controlled-release formulations can be used to control a drug's onset of action, duration of action, plasma levels within the therapeutic window, and peak blood levels.
  • controlled- or extended-release dosage forms or formulations can be used to ensure that the maximum effectiveness of a drug is achieved while minimizing potential adverse effects and safety concerns, which can occur both from under dosing a drug (i.e., going below the minimum therapeutic levels) as well as exceeding the toxicity level for the drug.
  • Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.
  • a variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the celecoxib and valdecoxib salts and compositions ofthe invention. Examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185 Bl; each of which is inco ⁇ orated herein by reference.
  • dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS® (Alza Co ⁇ oration, Mountain View, Calif. USA)), multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
  • ion exchange materials can be used to prepare immobilized, adsorbed salt forms of celecoxib and valdecoxib and thus effect controlled delivery of the drug.
  • One embodiment of the invention encompasses a unit dosage form which comprises a pharmaceutically acceptable salt of celecoxib or valdecoxib (e.g., a sodium, potassium, or lithium salt), or a polymo ⁇ h, solvate, hydrate, dehydrate, co- crystal, anhydrous, or amo ⁇ hous form thereof, and one or more pharmaceutically acceptable excipients or diluents, wherein the pharmaceutical composition or dosage form is formulated for controlled-release.
  • Specific dosage forms utilize an osmotic drug delivery system. A particular and well-known osmotic drug delivery system is refened to as
  • OROS® Alza Co ⁇ oration, Mountain View, Calif. USA. This technology can readily be adapted for the delivery of compounds and compositions ofthe invention.
  • Various aspects ofthe technology are disclosed in U.S. Pat. Nos. 6,375,978 Bl; 6,368,626 Bl; 6,342,249 Bl; 6,333,050 B2; 6,287,295 Bl; 6,283,953 Bl; 6,270,787 Bl; 6,245,357 Bl; and 6,132,420; each of which is inco ⁇ orated herein by reference.
  • OROS® that can be used to administer compounds and compositions of the invention
  • OROS® Push-PullTM Delayed Push- PullTM
  • Multi-Layer Push-PullTM Multi-Layer Push-PullTM
  • Push-StickTM Systems all of which are well known. See, e.g., http://www.alza.com.
  • Additional OROS® systems that can be used for the controlled oral delivery of compounds and compositions ofthe invention include OROS ⁇ -CT and L-OROS®. Id.; see also, Delivery Times, vol. II, issue II (Alza Co ⁇ oration).
  • OROS® oral dosage forms are made by compressing a drug powder (e.g., celecoxib or valdecoxib salt) into a hard tablet, coating the tablet with cellulose derivatives to form a semi-permeable membrane, and then drilling an orifice in the coating (e.g., with a laser).
  • a drug powder e.g., celecoxib or valdecoxib salt
  • Kim Cherng-ju, Controlled Release Dosage Form Design, 231-238 (Technomic Publishing, Lancaster, Pa.: 2000).
  • the advantage of such dosage forms is that the delivery rate ofthe drug is not influenced by physiological or experimental conditions. Even a drug with a pH-dependent solubility can be delivered at a constant rate regardless ofthe pH ofthe delivery medium.
  • a specific dosage form ofthe invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion ofthe wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion ofthe wall; a dry or substantially dry state drag layer located within the cavity adjacent to the exit orifice and in direct or indirect contacting relationship with the expandable layer; and a flow-promoting layer inte ⁇ osed between the inner surface ofthe wall and at least the external surface ofthe drug layer located within the cavity, wherein the drug layer comprises a salt of celecoxib, valdecoxib, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof. See U.S. Pat. No. 6,368,626, the entirety of which is inco ⁇ orated herein by reference.
  • Another specific dosage form ofthe invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion ofthe wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drag layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted drug layer without significant exudation ofthe liquid, active agent formulation, the dosage form optionally having a placebo layer between the exit orifice and the drug layer, wherein the active agent formulation comprises a salt of celecoxib, valdecoxib, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof. See U.S. Pat No. 6,342,2
  • multiple pellets can be inco ⁇ orated into the formulation, each with a distinct coating thickness. This will allow each pellet to dissolve at an exclusive, predetermined time interval following administration. The result is an increased duration ofthe desired therapeutic effect.
  • a controlled-release (CR) formulation can reduce the frequency at which a pharmaceutical must be administered to a patient, thereby decreasing the total amount of drug intake. Improvements such as reduced side effects, reduced drug accumulation, and reduced fluctuations in blood serum level are advantages of controlled-release formulations.
  • a further embodiment allows the formulation to include more than one therapeutic agent. Pellets of two or more APIs can be inco ⁇ orated, each with distinct coating thicknesses, thereby resulting in binary, tertiary, or higher order pharmaceuticals.
  • compositions intended to supply a gradual and controlled release in time ofthe active ingredient is well known in the pharmaceutical technology field.
  • Systems are known comprising tablets, capsules, microcapsules, microspheres and formulations in general, in which the active ingredient is released gradually by various means including the following.
  • Particles containing the API can be coated with individual specific external coatings so that the release of active medicament from the inner core is separated by sequential intervals.
  • the number of defined pulses of drag released by a formulation can range from about 1 to about 10, or more specifically from about 1 to about 5.
  • a drug-free lag time can be instituted before the release of first dosage ofthe active medicament. This drug-free lag time is accomplished by delaying the first pulse-release.
  • the dosage forms ofthe present invention may optionally be coated with one or more materials suitable for the regulation of release or for the protection of the formulation.
  • coatings are provided to permit either pH-dependent or pH-independent release, e.g., when exposed to gastrointestinal fluid.
  • a pH- dependent coating serves to release the API in desired areas ofthe gastro-intestinal (GI) tract, e.g., the stomach or small intestine, such that an abso ⁇ tion profile is provided which is capable of providing at least about eight hours and preferably about twelve hours to up to about twenty-four hours of analgesia to a patient.
  • the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the GI tract. It is also possible to formulate compositions which release a portion ofthe dose in one desired area ofthe GI tract, e.g., the stomach, and release the remainder ofthe dose in another area ofthe GI tract, e.g., the small intestine.
  • Formulations according to the invention that utilize pH-dependent coatings to obtain formulations may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract.
  • Coatings which are pH-dependent may be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PNAP), hydroxypropylmethylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like.
  • the substrate e.g., tablet core bead, matrix particle
  • the substrate containing the API is coated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.
  • the coating may be applied in the form of an organic or aqueous solution or dispersion.
  • the coating may be applied to obtain a weight gain from about 2 to about 25% ofthe substrate in order to obtain a desired sustained release profile. Coatings derived from aqueous dispersions are described in detail in U.S. Pat. ⁇ os. 5,273,760 and 5,286,493, and are hereby inco ⁇ orated by reference in their entirety.
  • sustained release formulations and coatings which may be used in accordance with the present invention include U.S. Pat. ⁇ os. 5,324,351, 5,356,467, and 5,472,712, also hereby inco ⁇ orated by reference in their entirety.
  • Cellulosic materials and polymers provide hydrophobic materials well suited for coating the beads according to the invention.
  • one prefened alkylcellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkylcellulose polymers may be readily employed, singly or in any combination, as all or part of a hydrophobic coating according to the invention.
  • One commercially-available aqueous dispersion of ethylcellulose is Aquacoat®
  • Aquacoat® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not inco ⁇ orated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat® with a suitable plasticizer prior to use.
  • Surelease® Colorcon, Inc., West Point, Pa., U.S.A.
  • This product is prepared by inco ⁇ orating plasticizer into the dispersion during the manufacturing process.
  • a hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.
  • the hydrophobic material comprising the controlled release coating is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate co-polymers.
  • acrylic acid and methacrylic acid copolymers including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate
  • the acrylic polymer is comprised of one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers arc well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • methacrylic acid ester-type polymers are useful for preparing pH- dependent coatings which may be used in accordance with the present invention.
  • methacrylic acid copolymer or polymeric methacrylates commercially available as Eudragit® from Rohm Tech, Inc.
  • Eudragit® E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media.
  • Eudragit® L is a methacrylic acid copolymer which does not swell at about pH ⁇ 5.7 and is soluble at about pH >6.
  • Eudragit® S does not swell at about pH ⁇ 6.5 and is soluble at about pH >7.
  • Eudragit® RL and Eudragit® RS are water swellable, and the amount of water absorbed by these polymers is pH-dependent, however, dosage forms coated with Eudragit® RL and RS are pH-independent.
  • the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively.
  • Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D.
  • the mean molecular weight is about 150,000.
  • the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents.
  • Eudragit® RL/RS mixtares are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the Eudragit® RL/RS dispersions ofthe present invention may be mixed together in any desired ratio in order to ultimately obtain a sustained release formulation having a desirable dissolution profile. Desirable sustained release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Of course, one skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit® L.
  • the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties ofthe sustained release coating.
  • a plasticizer into an ethylcellulose coating containing sustained release coating before using the same as a coating material.
  • the amount of plasticizer included in a coating solution is based on the concentration ofthe film-former, e.g., most often from about 1 to about 50 percent by weight ofthe film-former. Concentration ofthe plasticizer, however, can only be properly determined after careful experimentation with the particular coating solution and method of application.
  • plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used.
  • Triethyl citrate is an especially prefened plasticizer for the aqueous dispersions of ethyl cellulose ofthe present invention.
  • plasticizers for the acrylic polymers ofthe present invention include, but are not limited to citric acid esters such as triethyl citrate, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol.
  • Other plasticizers which have proved to be suitable for enhancing the elasticity ofthe films formed from acrylic films such as Eudragit® RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.
  • Triethyl citrate is an especially prefened plasticizer for the aqueous dispersions of ethyl cellulose ofthe present invention.
  • a plurality ofthe resultant solid controlled release beads may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by an environmental fluid, e.g., gastric fluid or dissolution media.
  • an environmental fluid e.g., gastric fluid or dissolution media.
  • the controlled release bead formulations of the present invention slowly release the therapeutically active agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids.
  • the controlled release profile ofthe formulations ofthe invention can be altered, for example, by varying the amount of overcoating with the hydrophobic material, altering the manner in which the plasticizer is added to the hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.
  • the dissolution profile ofthe ultimate product may also be modified, for example, by increasing or decreasing the thickness ofthe retardant coating.
  • Spheroids or beads coated with a therapeutically active agent are prepared, e.g., by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate, for example, using a Wuster insert.
  • additional ingredients are also added prior to coating the beads in order to assist the binding ofthe API to the beads, and/or to color the solution, etc.
  • a product which includes hydroxypropylmethylcellulose, etc. with or without colorant e.g., Opadry®, commercially available from Colorcon, Inc.
  • the resultant coated substrate in this example beads, may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled release coating.
  • a barrier agent is one which comprises hydroxypropylmethylcellulose.
  • any film-former known in the art may be used. It is prefened that the barrier agent does not affect the dissolution rate ofthe final product.
  • the beads may then be overcoated with an aqueous dispersion ofthe hydrophobic material.
  • the aqueous dispersion of hydrophobic material preferably further includes an effective amount of plasticizer, e.g. triethyl citrate.
  • plasticizer e.g. triethyl citrate.
  • pre-formulated aqueous dispersions of acrylic polymers such as Eudragit® can be used.
  • the coating solutions ofthe present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (i.e., water), a colorant to provide elegance and product distinction.
  • Color may be added to the solution ofthe therapeutically active agent instead, or in addition to the aqueous dispersion of hydrophobic material.
  • color may be added to Aquacoat® via the use of alcohol or propylene glycol based color dispersions, milled, aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low shear to the plasticized Aquacoat®.
  • any suitable method of providing color to the formulations ofthe present invention may be used.
  • Suitable ingredients for providing color to the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxide pigments. The inco ⁇ oration of pigments, may, however, increase the retard effect ofthe coating.
  • Plasticized hydrophobic material may be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment known in the art.
  • a Wurster fluidized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer coating is sprayed on.
  • a further overcoat of a film-former such as Opadry®, is optionally applied to the beads. This overcoat is provided, if at all, in order to substantially reduce agglomeration ofthe beads.
  • the release ofthe therapeutically active agent from the controlled release formulation ofthe present invention can be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating.
  • the ratio of hydrophobic material to water soluble material is determined by, among other factors, the release rate required and the solubility characteristics of the materials selected.
  • the release-modifying agents which function as pore-formers may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.
  • the pore-formers may comprise one or more hydrophilic materials such as hydroxypropylmethylcellulose.
  • sustained release coatings ofthe present invention can also include erosion- promoting agents such as starch and gums.
  • the sustained release coatings ofthe present invention can also include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain.
  • the release-modifying agent may also comprise a semi-permeable polymer.
  • the release-modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtares of any ofthe foregoing.
  • the sustained release coatings ofthe present invention may also include an exit means comprising at least one passageway, orifice, or the like.
  • the passageway may be formed by such methods as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of which are hereby inco ⁇ orated by reference).
  • the passageway can have any shape such as round, triangular, square, elliptical, inegular, etc.
  • the present invention may include dual-release compositions whereby a celecoxib salt is formulated so as to contain both a fast acting component and a sustained release component of drug delivery. This formulation allows for both relatively fast and prolonged therapeutic effects while minimizing administration frequency. Dual-release compositions are further described in WO 01/45706 Al, the contents of which are herein inco ⁇ orated by reference in their entirety.
  • Celecoxib compositions useful in methods of the present invention can be used in combination therapies with opioids and other analgesics.
  • the compound to be administered in combination with a celecoxib composition useful in methods ofthe invention can be formulated separately from said composition or co-formulated with said composition.
  • celecoxib composition is co-formulated with a second drug, for example an opioid drag
  • the second drag can be formulated in immediate-release, rapid-onset, sustained-release or dual-release form.
  • celecoxib can be combined with an anti-platelet drag for example, but not limited to, tirofiban, aspirin, dipyridamole, anagrelide, epoprostenol, eptifibatide, clopidogrel, cilostazol, abciximab, or ticlopidine.
  • Pharmaceutical compositions ofthe invention are useful in treatment and prevention of a very wide range of disorders mediated by COX-2, including but not restricted to disorders characterized by inflammation, pain and/or fever.
  • compositions of the invention are especially useful as anti-inflammatory agents, such as in treatment of arthritis, with the additional benefit of having significantly less harmful side effects than compositions of conventional non-steroidal anti-inflammatory drugs (NSAIDs) that lack selectivity for COX-2 over COX-1.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • pharmaceutical compositions ofthe invention have reduced the potential for gastrointestinal toxicity and gastrointestinal irritation including upper gastrointestinal ulceration and bleeding, reduced potential for renal side effects such as reduction in renal function leading to fluid retention and exacerbation of hypertension, reduced effect on bleeding times including inhibition of platelet function, and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects, by comparison with compositions of conventional NSAIDs.
  • compositions ofthe invention are particularly useful as an alternative to conventional NSAIDs where such NSAIDs are confraindicated, for example in subjects with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; gastrointestinal bleeding, coagulation disorders including anemia such as hypoprothrombinemia, hemophilia or other bleeding problems, kidney disease, or in subjects prior to surgery or subjects taking anticoagulants.
  • NSAIDs are confraindicated, for example in subjects with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; gastrointestinal bleeding, coagulation disorders including anemia such as hypoprothrombinemia, hemophilia or other bleeding problems, kidney disease, or in subjects prior to surgery or subjects taking anticoagulants.
  • Contemplated pharmaceutical compositions are useful to treat a variety of arthritic disorders, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.
  • Such pharmaceutical compositions are useful in treatment of asthma, bronchitis, menstrual cramps, preterm labor, tendonitis, bursitis, allergic neuritis, cytomegalovirus infectivity, apoptosis including HIN-induced apoptosis, lumbago, liver disease including hepatitis, skin-related conditions such as psoriasis, eczema, acne, burns, dermatitis and ultraviolet radiation damage including sunburn, and post-operative inflammation including that following ophthalmic surgery such as cataract surgery or refractive surgery.
  • compositions ofthe present invention are useful to treat gastrointestinal conditions such as, but not limited to, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.
  • Such pharmaceutical compositions are useful in treating inflammation in such diseases as migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury including brain edema, myocardial ischemia, and the like.
  • diseases as migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet'
  • compositions are useful in treatment of ophthalmic diseases, such as retinitis, conjunctivitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue.
  • ophthalmic diseases such as retinitis, conjunctivitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue.
  • compositions are useful in treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis, and in bone reso ⁇ tion such as that associated with osteoporosis.
  • the pharmaceutical compositions are useful for treatment of certain central nervous system disorders, such as cortical dementias including Alzheimer's disease, neurodegeneration, and central nervous system damage resulting from stroke, ischemia and trauma.
  • treatment in the present context includes partial or total inhibition of dementias, including Alzheimer's disease, vascular dementia, multi-infarct dementia, pre-senile dementia, alcoholic dementia and senile dementia.
  • compositions of the present invention are useful in treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome and liver disease. Further, pharmaceutical compositions ofthe present invention are useful in treatment of pain, including but not limited to postoperative pain, dental pain, muscular pain, and pain resulting from cancer.
  • compositions are useful for relief of pain, fever and inflammation in a variety of conditions including rheumatic fever, influenza and other viral infections including common cold, low back and neck pain, dysmenonhea, headache, oothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, bums, and trauma following surgical and dental procedures.
  • rheumatic fever influenza and other viral infections including common cold, low back and neck pain, dysmenonhea, headache, oothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, bums, and trauma following surgical and dental procedures.
  • the present invention is further directed to a therapeutic method of treating a condition or disorder where treatment with a COX-2 inhibitory drug is indicated, the method comprising oral administration of a pharmaceutical composition ofthe invention to a subject in need thereof.
  • the dosage regimen to prevent, give relief from, or ameliorate the condition or disorder preferably conesponds to once-a-day or twice-a- day treatment, but can be modified in accordance with a variety of factors. These include the type, age, weight, sex, diet and medical condition ofthe subject and the nature and severity ofthe disorder.
  • the dosage regimen actually employed can vary widely and can therefore deviate from the prefened dosage regimens set forth above.
  • compositions can be used in combination with other therapies or therapeutic agents, including but not limited to, therapies with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e. non-addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, GAB A active agents, norexin neuropeptide modulators, Substance P antagonists, neurokinin-1 receptor antagonists and sodium channel blockers, among others.
  • therapies with opioids and other analgesics including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e. non-addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, GAB A active agents, norexin neuropeptide modulators, Substance P antagonists, neurokinin-1 receptor antagonists and sodium
  • Prefened combination therapies comprise use of a composition ofthe invention with one or more compounds selected from aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine, alclofenac, alfentanil, allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate), amfenac, aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylon, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine, antipyrine salicylate, antrafenine, apazone, bendazac, benorylate, benoxa
  • compositions ofthe present invention are useful for treating and preventing inflammation-related cardiovascular disorders, including vascular diseases, coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including cardiac transplant atherosclerosis, myocardial infarction, embolism, stroke, thrombosis including venous thrombosis, angina including unstable angina, coronary plaque inflammation, bacterial-induced inflammation including Chlamydia-induced inflammation, viral induced inflammation, and inflammation associated with surgical procedures such as vascular grafting including coronary artery bypass surgery, revascularization procedures including angioplasty, stent placement, endarterectomy, or other invasive procedures involving arteries, veins and capillaries.
  • vascular diseases including coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including cardiac transplant atherosclerosis, myocardial infarction, embolism, stroke, thrombosis including venous thrombosis, angina including unstable angina, coronar
  • compositions are also useful in treatment of angiogenesis- related disorders in a subject, for example to inhibit tumor angiogenesis.
  • Such pharmaceutical compositions are useful in treatment of neoplasia, including metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, macular degeneration, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemangiomas, including infantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; and disorders ofthe female reproductive system such as endometriosis.
  • compositions ofthe present invention are useful in prevention and treatment of benign and malignant tumors and neoplasia including cancer, such as colorectal cancer, brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body.
  • cancer such as colorectal cancer, brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer,
  • Neoplasias for which compositions ofthe invention are contemplated to be particularly useful are gastrointestinal cancer, Banett's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer.
  • Such pharmaceutical compositions can also be used to treat fibrosis that occurs with radiation therapy.
  • These pharmaceutical compositions can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP).
  • FAP familial adenomatous polyposis
  • pharmaceutical compositions ofthe present invention can be used to prevent polyps from forming in subjects at risk of FAP.
  • compositions inhibit prostanoid-induced smooth muscle contraction by inhibiting synthesis of contractile prostanoids and hence can be of use in treatment of dysmenonhea, premature labor, asthma and eosinophil-related disorders. They also can be of use for decreasing bone loss particularly in postmenopausal women (i.e., treatment of osteoporosis), and for treatment of glaucoma.
  • Prefened uses for pharmaceutical compositions ofthe invention are for treatment of rheumatoid arthritis and osteoarthritis, for pain management generally (particularly post-oral surgery pain, post-general surgery pain, post-orthopedic surgery pain, and acute flares of osteoarthritis), for treatment of Alzheimer's disease, and for colon cancer chemoprevention.
  • a particular prefened use is for rapid pain management, such as when a celecoxib salt or a pharmaceutical composition thereof is effective in treating pain within about 30 minutes or less.
  • pharmaceutical compositions ofthe invention are useful for veterinary treatment of companion animals, exotic animals, farm animals, and the like, particularly mammals. More particularly, pharmaceutical compositions ofthe invention are useful for treatment of COX-2 mediated disorders in horses, dogs, and cats. ,
  • the sample was either left in the glass vial in which it was processed or an aliquot of the sample was fransfened to a glass slide.
  • the glass vial or slide was positioned in the sample chamber.
  • the measurement was made using an AlmegaTM Dispersive Raman (AlmegaTM Dispersive Raman, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495) system fitted with a 785 nm laser source.
  • the sample was manually brought into focus using the microscope portion of the apparatus with a lOx power objective (unless otherwise noted), thus directing the laser onto the surface ofthe sample.
  • the spectrum was acquired using the parameters outlined in Table 1. (Exposure times and number of exposures may vary; changes to parameters will be indicated for each acquisition.)
  • Each spectrum in a set was filtered using a matched filter of feature size 25 to remove background signals, including glass contributions and sample fluorescence. This is particularly important as large background signal or fluorescence limit the ability to accurately pick and assign peak positions in the subsequent steps of the binning process.
  • Filtered spectra were binned using the peak pick and bin algorithm with the parameters given in Table 2.
  • the sorted cluster diagrams for each sample set and the conesponding cluster assignments for each spectral file were used to identify groups of samples with similar spectra, which was used to identify samples for secondary analyses.
  • precipitate can be amo ⁇ hous or crystalline.
  • the loaded capillary was mounted in a holder that was secured into the x-y stage.
  • a diffractogram was acquired (e.g., Control software: RJNT Rapid Control Software, Rigaku Rapid/XRD, version 1.0.0, ⁇ 1999 Rigaku Co.) under ambient conditions at a power setting of 46 kV at 40 mA in reflection mode, while oscillating about the omega-axis from 0 - 5 degrees at 1 degree/s and spinning about the phi-axis at 2 degrees/s.
  • the exposure time was 15 minutes unless otherwise specified.
  • the diffractogram obtained was integrated over 2- theta from 2-60 degrees and chi (1 segment) from 0-360 degrees at a step size of 0.02 degrees using the cyllnt utility in the RINT Rapid display software (Analysis software: RINT Rapid display software, version 1.18, Rigaku/MSC.) provided by Rigaku with the instrument.
  • the dark counts value was set to 8 as per the system calibration (System set-up and calibration by Rigaku); normalization was set to average; the omega offset was set to 180°; and no chi or phi offsets were used for the integration.
  • the analysis software JADE XRD Pattern Processing, versions 5.0 and 6.0 8 1995-2002, Materials Data, Inc. was also used.
  • the relative intensity of peaks in a diffractogram is not necessarily a limitation ofthe PXRD pattern because peak intensity can vary from sample to sample, e.g., due to crystalline impurities.
  • the angles of each peak can vary by about +/- 0.1 degrees, preferably +/-0.05.
  • the entire pattern or most ofthe pattern peaks may also shift by about +/- 0.1 degree due to differences in calibration, settings, and other variations from instrument to instrument and from operator to operator. Any one or combination of two, three, four, five, six, seven, eight, or more of reported 2-theta angle peaks listed in the examples or in a figure can be used to characterize a particular chemical species.
  • sample pan e.g., Pan part # 900786.091; lid part # 900779.901; TA Instraments, 109 Lukens Drive, New Castle, DE 19720
  • the sample pan was sealed either by crimping for dry samples or press fitting for wet samples (e.g., hydrated or solvated samples).
  • the sample pan was loaded into the apparatus (DSC: Q1000 Differential Scanning Calorimeter, TA Instruments, 109 Lukens Drive, New Castle, DE 19720), which is equipped with an autosampler, and a thermogram was obtained by individually heating the sample (e.g., Control software: Advantage for QW- Series, version 1.0.0.78, Thermal Advantage Release 2.0, ⁇ 2001 TA instruments - Water LLC) at a rate of 10 degrees C /min from Tmin (typically 20 degrees C) to T max (typically 300 degrees C) (Heating rate and temperatare range may vary, changes to these parameters will be indicated for each sample) using an empty aluminum pan as a reference.
  • DSC Differential Scanning Calorimeter, TA Instruments, 109 Lukens Drive, New Castle, DE 19720
  • a thermogram was obtained by individually heating the sample (e.g., Control software: Advantage for QW- Series, version 1.0.0.78, Thermal Advantage Release 2.0, ⁇ 2001 TA instruments - Water LLC) at a rate
  • Dry nifrogen e.g., Compressed nitrogen, grade 4.8, BOC Gases, 575 Mountain Avenue, Munay Hill, NJ 07974-2082
  • nifrogen e.g., Compressed nitrogen, grade 4.8, BOC Gases, 575 Mountain Avenue, Munay Hill, NJ 07974-2082
  • Thermal transitions were viewed and analyzed using the analysis software (Analysis Software: Universal Analysis 2000 for Windows 95/95/2000/NT, version 3. IE; Build 3.1.0.40, ⁇ 1991 - 2001TA instruments - Water LLC) provided with the instrument.
  • Thermograms were obtained by individually heating the sample at 10 degrees C /min from 25 degrees C to 300 degrees C (Heating rate and temperature range may vary, changes in parameters will be indicated for each sample) under flowing dry nitrogen (e.g., Compressed nitrogen, grade 4.8, BOC Gases, 575 Mountain Avenue, Munay Hill, NJ 07974-2082), with a sample purge flow rate of 60 mL/min and a balance purge flow rate of 40 mL/min.
  • Thermal transitions e.g. weight changes
  • the PXRD diffractogram for the compound prepared above is shown in Fig. 2.
  • the diffractogram has characteristic peaks that can be used to characterize the salt comprising any one, or any combination of any two, any three, any four, any five, any six, or any other combination of peaks at 2-theta angles in Fig. 2 including, for example, the peaks at 3.65, 8.95, 10.77, 11.43, 14.01, 17.19, 18.33, 19.47, 19.99, 20.61, 21.71, 22.57, and 25.81 degrees.
  • the slurry was filtered by suction filtration and rinsed with 2 mL of isopropanol. The solid was allowed to air dry before being gently ground to a powder.
  • the product was analyzed by PXRD, DSC, and TGA as in Example 1, but a 0.5 mm capillary was used to hold the sample in the PXRD experiment.
  • the compound lost 17.35 % weight between room temperature and 120 degrees C.
  • the DSC thermogram shows a broad endothermic region, which is consistent with a loss of volatile components with increasing temperature. The endotherm peaks at 66 degrees C.
  • the PXRD pattern peaks that can be used to characterize the salt include any one or combination comprising any two, any three, any four, any five, any six, any seven, any eight, any nine, any ten, any eleven, any twelve, or all thirteen 2-theta angles of 4.09, 4.99, 6.51, 7.07, 9.99, 11.59, 16.53 , 17.69 , 18.47, 19.13 , 20.11 , 20.95 , 22.67 degrees, or any one or combination of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 peaks of Fig. 62.
  • Synthesis 1 To a vial was added 29.64 mg celecoxib and 3.00 mL of 1 M sodium hydroxide. The celecoxib dissolved. After a time, the celecoxib precipitated from solution.
  • Synthesis 2 To a vial was added 7.10 mg celecoxib and 3.00 mL of 1 M sodium hydroxide. The celecoxib dissolved. Overnight, the celecoxib precipitated and formed white, needle-like crystals.
  • Synthesis 3 To a vial was added 17.6 mg celecoxib and 10 mL of 1 M sodium hydroxide. The celecoxib dissolved. The vial was placed in a beaker wrapped in aluminum foil and filled with a large tissue for insulation. The beaker was left and crystals formed within about 12-36 hours.
  • the product solids from syntheses 1 and 2 were combined and analyzed by PXRD, DSC, and TGA as in example 1, but a 0.5 mm capillary was used to hold the sample in the PXRD experiment.
  • the product salt was found to contain about 4 equivalents of water per equivalent of salt, although as stated herein the hydration state ofthe salt can vary depending on humidity, temperature, and other conditions.
  • TGA showed a weight loss of 14.9% as the temperature was increased from room temperature to 100 degrees C at 10 degrees C/min.
  • DSC analysis showed a large endothermic transition at 74 +/- 1.0 degrees C and a second broad and noisy endothermic transition at about 130 +/- 5.0 degrees C.
  • the PXRD pattern has peaks that can be used to characterize the salt by including any one or a combination comprising any two, any three, any four, any five, or all six 2-theta angle peaks of 3.6, 8.9, 9.6, 10.8, 11.4, and 20.0 degrees.
  • the sodium salt form (from Example 6) was compared with CELEBREX powder in terms of abso ⁇ tion in rats (Figs. 4A and 4B).
  • Fig. 4 A and 4B Pharmacokinetics in male Sprague-Dawley rats after 5 mg/kg oral doses ofthe celecoxib crystal form used in the marketed formulations and the sodium salt form are shown in Fig. 4 A and 4B. Solids were placed in size 9 gelatin capsules (To ⁇ ac) and dosed via gavage needle, followed by oral gavage of 1 mL water. CELEBREX granulation was fransfened from commercial 200 mg capsules. The sodium salt was blended with polyvinylpyrrolidone (e.g. PovidoneK30) in a 1 :4 mixtare. The plots are averages of plasma levels at each ofthe time points from plasma of 5 rats.
  • polyvinylpyrrolidone e.g. PovidoneK30
  • the PXRD pattern has characteristic peaks as shown in Fig. 13 A.
  • An intense peak can be seen at 19.85 with other peaks at 2-theta angles including but not limited to, 3.57, 10.69, 13.69, 20.43, 21.53 and 22.39.
  • the crystal can be characterized by any one, any two, any three, any four, any five, or all six ofthe peaks above, or any one or combination of any number 2-theta angles of Fig. 13 A.
  • the celecoxib salt of Example 6 was administered to dogs and compared to administration of commercially available celecoxib.
  • Six male beagle dogs aged 2-4 years old and weighing 8-12 kg were food-deprived but were given water.
  • Each ofthe dogs was administered 3 test doses as described below and allowed a one week washout period between doses.
  • the test doses were: (1) commercially available celecoxib in the form of CELEBREX at 1 milligrams per kilogram (mpk) combined with 70/30 PEG400/water which was administered intravenously, (2) oral dose of commercially available celecoxib in the form of CELEBREX at 5 mpk adjusted for each dog's weight in size 4 gelatin capsules, and (3) oral dose ofthe sodium salt ofthe present invention as prepared according to Example 6 at 5 mpk adjusted for each dog's weight in size 4 gelatin capsules.
  • Blood samples of approximately 2 mL in sodium heparin were obtained by jugular venipuncture at 0.25, 0.5, 1, 3, 4, 6, 8, 12, and 24 hours post-dose. Additional samples were obtained predose and at 0.08 hr for the IV study.
  • Plasma samples were immediately placed on ice and centrifuged within 30 minutes of collection. Plasma samples ( ⁇ 1.0 mL) were harvested and stored in 4 aliquots of 0.25 mL at -20 degrees C. Plasma samples were analyzed for celecoxib using an LC-MS/MS assay with a lower limit of quantitation of 5 ng/mL. Pharmacokinetic profiles of celecoxib in plasma were analyzed using the PhAST software Program (Version 2.3, Pheonix Life Sciences, Inc.). The absolute bioavailability (F) is reported for oral doses relative to the IV dose.
  • Fig. 5 shows the mean pharmacokinetic parameters (and standard deviations therefore) of celecoxib in the plasma of male dogs following a single oral or single intravenous dose of celecoxib or celecoxib sodium salt.
  • the maximum blood serum concenfration and bioavailability of orally-administered celecoxib sodium salt was about three- and two-fold greater, respectively, than a roughly equal dose of orally- administered celecoxib, and the maximum blood serum concentration of celecoxib sodium was reached 40% faster than for celecoxib.
  • Celecoxib Lithium Salt (MO-116-49 A) Data (Raman) A small quantity of collected sample was placed on a glass slide and mounted in the Thermo Nicolet Almega Dispersive Raman spectrometer. The sample capture was set to 6 background scans and 12 sample collection scans. The parameters used for this analysis were:
  • Results of Raman spectroscopy show multiple spectral peaks that can be used to characterize the salt. These include any one, any two, any three, any four, any five, any six, any seven, any eight, any nine, any ten, or any other combination of peaks of Figure 16, e.g., 1617.10, 1596.95, 1449.56, 1374.03, 1115.24, 1062.85, 976.50, 800.67, 740.91 and 633.94 cm “1 .
  • PXRD peaks that can be used to characterize the salt include any one, or combination of any two, any three, any four, any five, any six, any seven, any eight, any nine, any ten, any eleven, or any other combination of peaks from Fig. 17, e.g., 4.14, 9.04, 10.705, 12.47, 15.08, 15.75, 18.71, 19.64, 20.52, 21.55 and 23.00 degrees.
  • weight loss between 25 and 200 degrees C is 5.778%) weight loss between 25 and 200 degrees C. A shoulder in the data is seen at 80 degrees C. Weight loss before this point is due to unbound water. The weight loss between 80 and 200 degrees C is due to more closely bound water, and represents 0.64 equivalents of water.
  • Fig. 20 The results are depicted in Fig. 20 and show characteristic Raman shift (cm "1 ) peaks at positions including, but not limited to any one or combination of any two, any three, any four, or all five ofthe peaks: 1617.66, 1448.22, 1374.09, 976.28, and 801.60 cm “1 , or any combinations of 1, 2, 3, 4, 5, or more peaks of Fig. 20.
  • characteristic Raman shift cm "1
  • a small amount of collected sample was placed in a 0.3 mm glass PXRD tube.
  • the tube was placed in Rigaku D/Max Rapid PXRD set to Cu; 46 kV/40 mA; CoUimator: 0.3; Omega-axis oscillation, Pos(deg) 0-5, speed 1; Phi-axis spin, Pos 360, Speed 2; Collection time was 15 minutes.
  • the PXRD pattern has characteristic peaks as shown in Fig. 21. Peaks can be seen at 2-theta angles including, but not limited to, 4.03, 12.23, 15.35, and 19.79 degrees.
  • the crystal can be characterized by any one or combination of any two, any three, or all four ofthe above angles or any one or any number combination of 2-theta angles of Fig. 21.
  • Example 10 Example 10
  • 5.447 mg of collected sample was placed into a platinum TGA pan.
  • the pan was placed in TA Instruments Q500 TGA and heated 10 degree C/min to 90 degree C, held for 10 minutes, ramped 10 degree C/min to 300 degree C, and held for 10 minutes with 40 mL/min nifrogen purge gas.
  • the results are depicted in Fig. 22 and show a weight loss of about 4.9 wt % from 25 degrees C to 200 degrees C and a weight loss of about 2.9 wt % at a shoulder from about 70 degrees C to 200 degrees C. Initial weight loss before the shoulder is most likely due to the evaporation of methanol. The weight loss after the shoulder is most likely due to excess water.
  • Thermo Nicolet Almega Dispersive Raman spectrometer A small quantity of collected sample was placed on a glass slide and mounted in the Thermo Nicolet Almega Dispersive Raman spectrometer. The sample capture was set to 6 background scans and 12 sample collection scans. The parameters ofthe spectrometer were as follows:
  • Fig. 23 The results are depicted in Fig. 23 and show characteristic Raman shift (cm "1 ) peaks at positions including, but not limited to any one or a combination of any two, any three, any four, any five, any six, any seven, any eight, any nine, any ten, or all eleven ofthe peaks 1615.51, 1446.09, 1374.28, 1232.91, 1197.04, 1108.99, 1060.94, 973.01, 798.86, 739.82, or 633.37 cm “1 , or any one or combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more peaks of Fig. 23.
  • a small amount of collected sample was placed in a 0.3 mm glass PXRD tube.
  • the tube was placed into a Rigaku D/Max Rapid PXRD set to Cu; 46 kV/40 mA; CoUimator: 0.3; Omega-axis oscillation, Pos(deg) 0-5, speed 1; Phi-axis spin, Pos 360, Speed 2; Collection time was 15 minutes.
  • the results are depicted in Fig. 24.
  • a small quantity of collected sample was placed on a glass slide and mounted in the Thermo Nicolet Almega Dispersive Raman spectrometer.
  • the sample capture was set to 6 background scans and 12 sample collection scans.
  • Characteristic Raman shift (cm "1 ) peaks were observed at positions including, but not limited to, any one, any two, any three, any four, any five, any six, or all seven ofthe peaks 1616.99, 1598.42, 1450.05, 1376.57, 973.10, 800.62, 642.20, or any combinations of 2, 3, 4, 5, 6, 7 or more peaks of Fig. 26.
  • peaks ofthe free acid may also be found in the compositions ofthe present invention.
  • the peaks characteristic ofthe free acid as shown in Fig. 28, may also be specifically excluded from compositions ofthe present invention.
  • HPC hydroxypropylcellulose
  • the 96-well plates were sealed, and incubated to a temperature of 40 degrees C for 20 minutes. After incubation, the plate seals were removed.
  • Celecoxib pre-dissolved in potassium hydroxide to a concentration of 5.5 mg/mL, was dispensed in 15 microtiter aliquots to each well and immediately mixed. This gave a final celecoxib concentration of 0.5 mg/mL in each well. The final excipient concenfration was 1.8 mg/mL.
  • a nephelometer (Nephelostar Galaxy, BMG Technologies, Durham, NC), with a chamber preheated to 37 degrees C, was used to analyze the ability ofthe excipients to retard the crystallization/precipitation of supersatarated celecoxib.
  • the assay plate containing celecoxib and excipients was sealed using an optically clear seal and placed into the nephelometer instrument.
  • the nephelometer recorded changes in solution turbidity over a 1 hour time period.
  • Fig. 30 shows crystal retardation time for celecoxib as a function of excipient in simulated gastric fluid (SGF). Final concenfration of celecoxib was 0.5 mg/mL. Black bars indicate crystal retardation time that may be greater than 60 min. Excipients listed in Table 3, but excluded from Fig. 30 did not show any appreciable crystal retardation time (i.e., greater than 1.5 minutes). Nineteen of 58 excipients were found to retard recrystallization/precipitation of celecoxib. Interestingly, in contrast to the dissolution assay, Vitamin E TPGS alone had a longer retardation time than in combination with HPC, which alone did not show any retardation time.
  • the solubility of celecoxib free acid in Transcutol P is 350 mg/g. It was found that in contrast to enhancing solubility, Transcutol P does not enhance dissolution ofthe free acid. Transcutol P does extend the time to T max and increases the time the concentration of celecoxib is above Vi T max when used in combination with a precipitation retardant and enhancer. It was further found that dissolution of a salt form is far superior to the dissolution of compositions comprising the free acid.
  • PLURONIC polyxamer
  • properties can be significantly altered (i.e., melting point, cloud point, molecular weight, HLB number, surface tension, interfacial tension, etc.) by adjusting the ratio of copolymer blocks. Further examination of these properties showed that the surface tension of these copolymers at a 0.1 % concentration in water conelates with the ability to retard the crystallization/precipitation of celecoxib.
  • PLURONIC excipients having low interfacial tension i.e., less than about 10 dyne/cm
  • having a surface tension less ithen about 42 dyne/cm were more effective at keeping celecoxib in solution than PLURONIC excipients having high interfacial tension or surface tension.
  • This observation is illustrated in Fig. 31 , along with interfacial data for PLURONICs that were not tested. Based on this conelation, the supersaturation properties of these additional PLURONICs also conelate with interfacial tension.
  • Fig. 31 shows interfacial tension of selected PLURONIC excipients in water.
  • An interfacial tension threshold for crystal retardation was loosely defined as less than about 9 or 10 dyne/cm.
  • Excipient concentration in the assay was 0.18 %>; celecoxib concenfration was 0.5 mg/mL.
  • Celecoxib Preparation a. Fresh celecoxib sodium salt hydrate was prepared and analyzed to be approximately 90% free acid vs. sodium content. b. The celecoxib salt was ground using mortar and pestle until fine powder was formed. The fine powder was sieved using a 105 micrometer pore size mesh and stored in a 20 mL scintillation vial at room temperature.
  • a liquid excipient such as Poloxamer 124, Peg 200, or Peg 400 was added to the mortar as a granulating fluid-like liquid to form an intimate contact between drag and excipient.
  • the mixture was ground and mixed until a uniform consistency was observed in the solid-state mixtare.
  • Dissolution Assay a A water bath was set up at 37 degrees C. b. Simulated gastric fluid in the fasted state (SGF) was prepared at pH 1.7 and diluted five times with deionized water. The final pH was approximately 2.4. The simulated gastric fluid was diluted five times to simulate the effect of drinking a glass of water with the medication. The SGF was pre-heated to 37 degrees C. c. The formulation was placed in a 20 mL scintillation vial. d. A 10 mm x 3 mm stir bar was added. e. Diluted SGF was added to the formulation. The volume added was set to satisfy a 2 mg/mL dose of celecoxib free acid. f.
  • SGF gastric fluid in the fasted state
  • the vial was placed in the water bath and allowed to stir. g. At each time point, 0.9 mL of solution was extracted and filtered through a 0.2 micrometer polyvinylflouridine filter. The first 2/3 of filtrate was discarded as waste and the last 1/3 was collected into an eppendorf tube. 0.1 mL of the collected filtrate was immediately fransfened to an autosampler vial and diluted ten times with 0.9 mL of methanol. The autosampler vials were crimp sealed and submitted for content analysis using high performance liquid chromatography with ultraviolet detection.
  • PLURONIC P123 and F127 Dissolution of two PLURONIC excipients that had low interfacial tension: PLURONIC P123 and F127.
  • PLURONIC P123 was a paste at room temperatare, and resulted in sticky formulation of celecoxib salt.
  • PLURONIC F127 was a solid at room temperatare and formed a flowable powder solid-state mixture with the celecoxib salt. The dissolution result for these mixtares at equal weight concentrations of excipient to celecoxib free acid content are shown in Figure 32.
  • PLURONIC P123 gave enhanced dissolution of celecoxib salt, while PLURONIC F127 did not.
  • the poor performance of PLURONIC F 127 in enhancing celecoxib dissolution was due to the slow dissolution ofthe excipient.
  • Poloxamer 124 Equal weight ratios of celecoxib free acid content, PLURONIC F127, and HPC were formulated with 40-45%> celecoxib free acid weight of granulating fluid. The effect of these formulations on dissolution is shown in Fig. 34. The granulating fluid-like liquids increased the dissolution of celecoxib, possibly by delaying the contact between the celecoxib salt and the dissolution media until PLURONIC F127 had been dissolved to a significant extent.
  • Dissolution of celecoxib sodium hydrate was then measured from a compacted formulation containing PLURONIC F127 and HPC excipients.
  • Formulations containing equal weight ratios of celecoxib free acid content, PLURONIC F127, and HPC were mixed and compacted into 6 mm discs at 4900 psi.
  • the compaction process produced a similar effect on dissolution to that observed by the addition of a granulating fluid (see Fig. 34) with the addition of a controlled release mechanism.
  • the controlled release characteristic ofthe profile can be modulated by selecting HPC or HPMC with varying grades of viscosity and the addition of disintegrants into the compact.
  • Compacts are attractive formulations due to their lower production cost and fewer processing steps.
  • Excipients are dissolved to a desired concentration in de-ionized (DI) water or other media (i.e., simulated gastric or intestinal fluids).
  • DI de-ionized
  • API is dissolved in a suitable solvent in which it has high solubility (i.e., acidic pH environment for free base type API; and basic pH environment for free acid type API).
  • excipient solutions are dispensed into an assay plate (i.e., 96-well or 384- well optically clear plate) either manually or using automated liquid handling equipment.
  • the excipients can be added as single, binary, ternary, or higher order excipient combinations into each well.
  • An example of a liquid handling instrument is the Tecan Genesis (Tecan U.S. Inc, Research Triangle Park, NC).
  • the API solution is dispensed into the assay plate.
  • the API solution can be dispensed one well at a time, by rows, or columns using the Tecan Genesis instrument or simultaneously into all wells using the Tecan Genmate instrument.
  • the volume of API solution added is restricted to a small size to avoid causing any shifts in the properties ofthe excipient solution.
  • Birefringence screening, PXRD, etc. may be performed to determine if precipitated API is amo ⁇ hous or crystalline. If the API is crystalline, crystal habit and particle size can be recorded.
  • Informatics may be used to conelate successful excipients that retard nucleation with physical property information.
  • API final solid-state form analysis i.e., amo ⁇ hous, crystalline, habit
  • Fluid F was prepared in DI H 2 0 by mixing ingredients at twice the desired final concentration.
  • API solution was prepared at a concenfration of 5.5 mg/mL in Fluid C. 4.
  • the Tecan Genesis instrument was used to dispense a combination of 75 microliters Fluid F, 18.75 microliters excipient solution, and 56.25 microliters DI H 2 0 into each well of a 96-well plate. The final concentration of excipient in each well was 2 mg/mL in Fluid F. The total fluid volume per well was 150 microliters. Four replicate wells were used for each single excipient solution.
  • FIG. 37 An example ofthe layout is shown in Fig. 37.
  • the plate was sealed using a transparent seal (Part No. 6575; Corning Inco ⁇ orated, Coming, NY) and incubated at 40 degrees C for 20 minutes.
  • the well contents were mixed and sealed using the transparent seal (Part No. 6575; Corning Inco ⁇ orated, Corning, NY).
  • the plate was placed on the Nephelostar instrument to collect light scatter data over a 1 hour time period.
  • the Nephelostar incubated the plate at 37 degrees C as specified in the goal ofthe assay.
  • the threshold limit for the increase ofthe light scatter signal used to define a precipitation/crystallization event is usually set at three times the standard deviation ofthe baseline signal to take into account background noise. The threshold can be set however, to a different value depending on the sensitivity of the assay and the desired limit of precipitation crystallization.
  • Non-limiting examples of alternatives to this general method include:
  • Retardation time can be measured as a function of excipient concentration.
  • Retardation time can be measured as a function of API salt or co-crystal concentration.
  • API can be concentrated in a non-aqueous medium prior to assay.
  • test excipient can be mixed with the API in the compound solution prior to combining with the aqueous/SGF/SIF or other test solution (which is the excipient solution minus the excipient).
  • Fig. 39 shows the results of TGA. A weight loss of about 15.6% was observed between about 65 and 200 degrees C.
  • Fig. 40 shows the results of PXRD. Peaks, in 2-theta angles, that can be used to characterize the solvate include any 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ofthe following: 3.77, 7.57, 8.21, 11.33, 14.23, 16.15, 18.69, 20.63, 22.69 and 24.77 degrees or any one or any combination of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks of Fig. 40. The other peaks ofthe graphs may also be used alone or in any combination to characterize the solvate.
  • Example 19 Example 19
  • a propylene glycol solvate ofthe potassium salt of celecoxib was prepared. To a solution of celecoxib (253 mg, 0.664 mmol) in Et 2 O (6 mL) was added propylene glycol (0.075 mL, 1.02 mmol). To the clear solution was added KOtBu in THF (1 M, 0.66 mL, 0.66 mmol). Crystals immediately began to form. After 5 minutes, the solid had completely crystallized. The solid was collected by filtration and was washed with Et 2 0 (10 mL). The white solid was then air-dried and collected. This solid was a 1 : 1 solvate. The solid was characterized by TGA and PXRD. The results are depicted in Fig. 41 and 42.
  • Fig. 41 shows the results of TGA. A weight loss of about 14.94% was observed between about 65 and about 250 degrees C.
  • Fig. 42 shows the results of PXRD. Peaks, in 2-theta angles, that can be used to characterize te solvate include any 1, 2, 3, 4, 5, 6, 7, 8 , 9, or 10 of the following: 3.75, 7.47, 11.33, 14.93, 15.65, 18.31, 20.47, 21.71, 22.51, and 24.97 degrees or any one or any combination of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks of Fig. 42.
  • a propylene glycol solvate ofthe lithium salt of celecoxib was prepared. To a solution of celecoxib (264 mg, 0.693 mmol) in Et 2 O (8 mL) was added propylene glycol (0.075 mL, 1.02 mmol). To the clear solution was added tBu-Li in pentane (1.7 M, 0.40 mL, 0.68 mmol). A brown solid formed immediately but dissolved within one minute yielding a white solid. The white solid crystallized completely after 10 minutes. The solid was collected by filtration and was washed with Et 2 O (10 mL). The white solid was then air-dried and collected. The solid was a 1 : 1 solvate. The solid was characterized by TGA and PXRD. The results of TGA are depicted in Fig. 43 and show a weight loss of about
  • Characteristic peaks of 2-theta angles that can be used to characterize the salt include any one, or combination of any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of 3.79, 7.51, 8.19, 9.83, 11.41, 15.93, 18.29, 19.19, 19.87, 20.63, 22.01, or 25.09 degrees or any one or any combination of peaks of Fig. 51.
  • Celecoxib Na propylene glycol trihydrate was formed by allowing the celecoxib sodium salt propylene glycol solvate to sit at 60 % RH and 20 degrees C for 3 days. (Note: Formation ofthe trihydrate at 75 % and 40 degrees C as well). The trihydrate begins to form somewhere between 31 and 40 % RH at room temperature.
  • the results of TGA and PXRD are shown in Fig. 44 and 45.
  • Fig. 44 shows the results of TGA where an about 9.64%> weight loss was observed between room temperature and 60 degrees C and an about 13.6% weight loss was observed between about 60 degrees C and 175 degrees C.
  • the PXRD pattern has characteristic peaks at 2-theta angles shown in Fig. 45.
  • the trihydrate can also be formed by crystallization of celecoxib Na propylene glycol solvate in the presence of H 2 0.
  • Fig. 46 shows the results of TGA where an about 10.92% weight loss was observed between room temperature and 50 degrees C and an about 12.95% weight loss was observed between about 50 degrees C and 195 degrees C.
  • the PXRD pattern has characteristic peaks at 2-theta angles shown in Fig. 47. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more peaks can be used to characterize the trihydrate, including for example, peaks at 3.43, 6.95, 10.25, 13.95, 16.39, 17.39, 17.75, 18.21, 19.43, 21.21, 22.61, and 25.71 degrees.
  • FIG. 48 shows the results of DSC analysis where a peak endotherm was observed at 67.69 degrees C.
  • the PXRD pattern has characteristic peaks at 2-theta angles shown in Fig. 50.
  • any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more peaks can be used to characterize the solvate, including for example, peaks at 3.43, 7.03, 10.13, 11.75, 14.11, 16.61, 17.61, 18.49, 19.51, 20.97, 22.33, 22.81, and 25.93 degrees.
  • Celecoxib 100 mg, 0.26 mmol
  • nicotinamide 32.0 mg, 0.26 mmol
  • the two solutions were mixed and the resulting mixture was allowed to evaporate slowly overnight.
  • the precipitated solid was collected and characterized.
  • Detailed characterization ofthe co-crystal was performed using DSC, TGA & PXRD.
  • the results of DSC showed two phase transitions at 117.2 and 118.8 degrees C and a sha ⁇ endotherm at 129.7 degrees C.
  • the results of TGA showed decomposition beginning at ⁇ 150 degrees C.
  • the results of PXRD is shown in Fig. 52.
  • Characteristic peaks that can be used to characterize the co-crystal include any one, or any combination of any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 the peaks at 3.77, 7.56, 9.63, 14.76, 16.01, 17.78, 18.68, 19.31, 20.435, 21.19, 22.10, 23.80, 24.70, 25.295, and 26.73 de rees, or any one or any combination of any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more peaks of Fig. 52.
  • the celecoxib sodium is a variable hydrate.
  • the celecoxib sodium salt and celecoxib sodium salt propylene glycol solvate were analyzed by PXRD under 17 %, 31 %, 59 % and 74 % constant relative humidity at room temperatare.
  • the following table lists PXRD 2- theta angle (degrees) peaks at the different relative humidities.
  • composition can be characterized by any one or combination of any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more peaks listed in Table 4 or any one or combination of any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more peaks of any one of Figs. 53-60.
  • Fig. 53-56 are PXRD diffractograms of celecoxib sodium hydrates at 17 %, 31 %, 59 %, and 74 % RH, respectively.
  • Fig. 57-60 are PXRD diffractograms of celecoxib sodium propylene glycol hydrates at 17 %, 31 %>, 59 %>, and 74 % RH, respectively.
  • PXRD PXRD.
  • the PXRD patterns were then grouped based on shared peaks. Several groups were identified with four shown in Fig. 61. Group D is consistent with a mixtare of amo ⁇ hous and crystalline celecoxib sodium. Table 5 lists PXRD peaks characteristic in common to groups A, B, and C and peaks that are specific to each group.
  • Valdecoxib isopropanol solvate is characterized by a very broad endothermic transition observed by differential scanning calorimetry (DSC) between 60 and 150 degrees C, and sha ⁇ endothermic transitions at 160 and 170 degrees C (Fig. 62). - I l l -
  • TGA showed the valdecoxib isopropanol solvate loses ⁇ 1 % of its weight between room temperatare and 50°C and 14-17 % of its weight between 50 and 150 degrees C (Fig. 63).
  • the valdecoxib isopropanol solvate When analyzed by Raman spectroscopy, the valdecoxib isopropanol solvate exhibited Raman shifts at about 1634.5, 1601.5, 1161, 1032.5, and 1006 cm “1 (Fig. 65).
  • the isopropanol solvate of valdecoxib (Example 26, 113.0 mg, 0.3189 mmol) was suspended in an aqueous solution of NaOH (3 mL, 1 M). The suspension was gently heated at 60 degrees C for 30 minutes to dissolve most ofthe solid, although some remained in suspension. The mixtare was allowed to cool to room temperatare, which yielded no precipitation. Further cooling to 4 degrees C also gave no precipitation ofthe product. The solvent (H 2 0) was evaporated resulting in a white solid. The solid was washed with H 2 0 (5 mL) and filtered to yield another white solid. The solid was allowed to air dry resulting in a white crystalline powder.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention concerne des procédés permettant de cribler des mélanges contenant un composé pharmaceutique et un excipient, afin d'identifier les propriétés de la combinaison composé pharmaceutique/excipient retardant la nucléation à l'état solide. La présente invention concerne également un procédé permettant d'augmenter la solubilité, la dissolution et la biodisponibilité d'un médicament présentant une solubilité faible dans des fluides gastriques; ce procédé consiste à combiner ledit médicament avec un retardateur de précipitation et avec un activateur éventuel.
PCT/US2003/028982 2002-02-15 2003-09-16 Compositions pharmaceutiques presentant une dissolution amelioree WO2004026235A2 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
AU2003267231A AU2003267231A1 (en) 2002-09-20 2003-09-16 Pharmaceutical compositions with improved dissolution
US10/528,244 US20060052432A1 (en) 2002-09-20 2003-09-16 Pharmaceutical compositions with improved dissolution
EP10193736A EP2339328A3 (fr) 2002-12-30 2003-12-24 Compositions pharmaceutiques cocrystallisees de celecoxib
PCT/US2003/041273 WO2004061433A1 (fr) 2002-12-30 2003-12-24 Compositions pharmaceutiques a dissolution amelioree
EP03808567A EP1579198A1 (fr) 2002-12-30 2003-12-24 Compositions pharmaceutiques a dissolution amelioree
CA2511881A CA2511881C (fr) 2002-12-30 2003-12-24 Compositions pharmaceutiques comprenant un sel de sodium de celecoxib a dissolution amelioree
US10/541,216 US8362062B2 (en) 2002-02-15 2003-12-24 Pharmaceutical compositions with improved dissolution
AU2003303591A AU2003303591A1 (en) 2002-12-30 2003-12-24 Pharmaceutical compositions with improved dissolution
JP2005508617A JP5021934B2 (ja) 2002-12-30 2003-12-24 改善された溶解性を有する医薬組成物
AU2003300452A AU2003300452A1 (en) 2002-12-30 2003-12-29 Pharmaceutical propylene glycol solvate compositions
PCT/US2003/041642 WO2004060347A2 (fr) 2002-09-03 2003-12-29 Compositions pharmaceutiques de solvates de propylene glycol

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US41245902P 2002-09-20 2002-09-20
US60/412,459 2002-09-20
US42627502P 2002-11-14 2002-11-14
US60/426,275 2002-11-14
US42708602P 2002-11-15 2002-11-15
US60/427,086 2002-11-15
US42951502P 2002-11-26 2002-11-26
US60/429,515 2002-11-26
US43751602P 2002-12-30 2002-12-30
US60/437,516 2002-12-30
US45602703P 2003-03-18 2003-03-18
US60/456,027 2003-03-18

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10541216 Continuation-In-Part 2003-12-24

Publications (2)

Publication Number Publication Date
WO2004026235A2 true WO2004026235A2 (fr) 2004-04-01
WO2004026235A3 WO2004026235A3 (fr) 2004-08-05

Family

ID=32034516

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/028982 WO2004026235A2 (fr) 2002-02-15 2003-09-16 Compositions pharmaceutiques presentant une dissolution amelioree

Country Status (3)

Country Link
US (1) US20060052432A1 (fr)
AU (1) AU2003267231A1 (fr)
WO (1) WO2004026235A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1755388A1 (fr) * 2004-05-28 2007-02-28 Transform Pharmaceuticals, Inc. Co-cristaux mixtes et compositions pharmaceutiques les renfermant
WO2012016111A1 (fr) * 2010-07-30 2012-02-02 Mcneil-Ppc, Inc. Forme hydratée de sel de sodium de celecoxib
WO2021158573A1 (fr) * 2020-02-03 2021-08-12 Natural Extraction Systems, LLC Procédés liés à des agents bioactifs qui convertissent des anions en molécules

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2489984A1 (fr) * 2002-06-21 2003-12-31 Transform Pharmaceuticals, Inc. Compositions pharmaceutiques a dissolution amelioree
US8183290B2 (en) 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen
CA2570949A1 (fr) * 2006-12-12 2008-06-12 Apotex Pharmachem Inc. Solvate d'ibandronate sodique et de propyleneglycol et methodes de preparation connexes
US7834195B2 (en) 2007-01-24 2010-11-16 Apotex Pharmachem Inc. Atorvastatin calcium propylene glycol solvates
SA109300195B1 (ar) 2008-03-28 2013-04-20 Astrazeneca Ab تركيبة صيدلانية جديدة مضادة للسرطان
GB0919757D0 (en) * 2009-11-12 2009-12-30 Johnson Matthey Plc Polymorphs of bromfenac sodium and methods for preparing bromfenac sodium polymorphs
US8299295B2 (en) 2009-10-15 2012-10-30 Johnson Matthey Public Limited Company Polymorphs of bromfenac sodium and methods for preparing bromfenac sodium polymorphs
US20180185378A1 (en) * 2017-01-05 2018-07-05 Cormedix Inc. Antimicrobial delivery system for the prevention and treatment of infections in the colon
WO2018035030A1 (fr) * 2016-08-15 2018-02-22 Corr-Jensen Inc. Principes actifs liposolubles à libération prolongée

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001041536A2 (fr) * 1999-12-08 2001-06-14 Pharmacia Corporation Celecoxib a l'etat solide ayant une biodisponibilite amelioree
WO2001041760A2 (fr) * 1999-12-08 2001-06-14 Pharmacia Corporation Compositions d'inhibiteur de cyclooxygenase-2 produisant rapidement un effet therapeutique

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5842168B2 (ja) * 1974-12-20 1983-09-17 トウコウヤクヒンコウギヨウ カブシキガイシヤ 局所用剤の製造方法
LU84515A1 (fr) * 1982-12-09 1984-10-22 Oreal Composition stable pour corticotherapie locale a forte concentration hydrocortisone solubilisee
US5286493A (en) * 1992-01-27 1994-02-15 Euroceltique, S.A. Stabilized controlled release formulations having acrylic polymer coating
US5472712A (en) * 1991-12-24 1995-12-05 Euroceltique, S.A. Controlled-release formulations coated with aqueous dispersions of ethylcellulose
US5273760A (en) * 1991-12-24 1993-12-28 Euroceltigue, S.A. Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US5324351A (en) * 1992-08-13 1994-06-28 Euroceltique Aqueous dispersions of zein and preparation thereof
CN1061036C (zh) * 1993-11-30 2001-01-24 G·D·瑟尔公司 用于治疗炎症的取代的吡唑基苯磺酰胺类化合物
US5466823A (en) * 1993-11-30 1995-11-14 G.D. Searle & Co. Substituted pyrazolyl benzenesulfonamides
WO1996025405A1 (fr) * 1995-02-13 1996-08-22 G.D. Searle & Co. Isoxazoles substitues utilisables dans le traitement d'inflammations
US5633272A (en) * 1995-02-13 1997-05-27 Talley; John J. Substituted isoxazoles for the treatment of inflammation
US5641512A (en) * 1995-03-29 1997-06-24 The Procter & Gamble Company Soft gelatin capsule compositions
TR199802049T2 (xx) * 1996-04-12 1999-01-18 G.D.Searle & Co. COX-2 Inhibit�rlerinin �nilac� olarak s�bstit�e edilmi� benzens�lfonamid t�revleri.
CA2232855C (fr) * 1997-04-10 2007-10-09 Roche Consumer Health (Worldwide) Sa Preparation pharmaceutique
US5972986A (en) * 1997-10-14 1999-10-26 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia
DE69922688T2 (de) * 1998-11-02 2005-12-01 Merck & Co. Inc. Zusammensetzungen aus einem 5ht1b/1d agonisten und einem selektiven cox-2 hemmer zur behandlung von migräne
RU2246295C2 (ru) * 1998-11-02 2005-02-20 Элзэ Копэрейшн Лекарственная форма c постоянной скоростью высвобождения лекарственного вещества, ядро лекарственной формы и способ обеспечения облегченного высвобождения лекарственного вещества из лекарственной формы
US6342249B1 (en) * 1998-12-23 2002-01-29 Alza Corporation Controlled release liquid active agent formulation dosage forms
US6294192B1 (en) * 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US6413965B1 (en) * 1999-06-30 2002-07-02 Pfizer Inc. Compositions and treatment for diabetic complications
CA2381895A1 (fr) * 1999-08-27 2001-03-08 Merck & Co., Inc. Methode de traitement ou de prevention de la prostatite chronique ou du syndrome de la douleur pelvienne chronique
US6323226B1 (en) * 1999-10-19 2001-11-27 Texas Heart Institute Treatment of heart disease with cox-2 inhibitors
EP1150959B1 (fr) * 1999-12-08 2008-02-27 Pharmacia Corporation Forme solide de celecoxib, presentant une biodisponibilite accrue
BR0008059A (pt) * 1999-12-08 2002-03-26 Pharmacia Corp Composições de valdecoxib
EP1239857B1 (fr) * 1999-12-22 2006-04-19 Pharmacia Corporation Compositions a liberation double d'un inhibiteur de cyclo-oxygenase-2
AU2731401A (en) * 1999-12-22 2001-07-03 Pharmacia Corporation Sustained-release formulation of a cyclooxygenase-2 inhibitor
EP1120109A3 (fr) * 2000-01-24 2002-07-10 Pfizer Products Inc. Formes posologiques solides à désintégration et dissolution rapide
JP2004500427A (ja) * 2000-04-18 2004-01-08 ファルマシア・コーポレーション 選択的シクロオキシゲナーゼ−２阻害薬の即効性製剤
MY120279A (en) * 2000-05-26 2005-09-30 Pharmacia Corp Use of a celecoxib composition for fast pain relief
TWI256305B (en) * 2000-08-18 2006-06-11 Pharmacia Corp Oral fast-melt pharmaceutical composition of a cyclooxygenase-2 inhibitor and process for preparing the same
JP2004506680A (ja) * 2000-08-18 2004-03-04 ファルマシア・コーポレーション シクロオキシゲナーゼ−２阻害剤の迅速崩壊経口製剤
US6688443B2 (en) * 2001-11-07 2004-02-10 L & P Property Management Company Apparatus and method for double clutch actuator

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001041536A2 (fr) * 1999-12-08 2001-06-14 Pharmacia Corporation Celecoxib a l'etat solide ayant une biodisponibilite amelioree
WO2001041760A2 (fr) * 1999-12-08 2001-06-14 Pharmacia Corporation Compositions d'inhibiteur de cyclooxygenase-2 produisant rapidement un effet therapeutique

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1755388A1 (fr) * 2004-05-28 2007-02-28 Transform Pharmaceuticals, Inc. Co-cristaux mixtes et compositions pharmaceutiques les renfermant
JP2008501024A (ja) * 2004-05-28 2008-01-17 トランスフオーム・フアーマシユーチカルズ・インコーポレーテツド 混合コクリスタルおよびそれを含んでなる製薬学的組成物
EP1755388A4 (fr) * 2004-05-28 2009-09-16 Transform Pharmaceuticals Inc Co-cristaux mixtes et compositions pharmaceutiques les renfermant
US7671093B2 (en) 2004-05-28 2010-03-02 Transform Pharmaceuticals, Inc. Mixed co-crystals and pharmaceutical compositions comprising the same
WO2012016111A1 (fr) * 2010-07-30 2012-02-02 Mcneil-Ppc, Inc. Forme hydratée de sel de sodium de celecoxib
US8410287B2 (en) 2010-07-30 2013-04-02 Mcneil-Ppc, Inc. Hydrated sodium salt form of celecoxib
WO2021158573A1 (fr) * 2020-02-03 2021-08-12 Natural Extraction Systems, LLC Procédés liés à des agents bioactifs qui convertissent des anions en molécules

Also Published As

Publication number Publication date
AU2003267231A8 (en) 2004-04-08
WO2004026235A3 (fr) 2004-08-05
US20060052432A1 (en) 2006-03-09
AU2003267231A1 (en) 2004-04-08

Similar Documents

Publication Publication Date Title
US8362062B2 (en) Pharmaceutical compositions with improved dissolution
EP1150959B1 (fr) Forme solide de celecoxib, presentant une biodisponibilite accrue
AU2002254609B2 (en) Orally deliverable pharmaceutical composition comprising an active compound having an aminosulfonyl group (COX-2 inhibitor), a polyethylene glycol and a free-radical scavenging antioxidant
AU2002254609A1 (en) Orally deliverable pharmaceutical composition comprising an active compound having an aminosulfonyl group (COX-2 inhibitor), a polyethylene glycol and a free-radical scavenging antioxidant
CZ20013210A3 (cs) Pevná forma celecoxibu mající zvýąenou biologickou dostupnost
CZ20013163A3 (cs) Prostředky obsahující valdecoxib
WO2001041536A2 (fr) Celecoxib a l'etat solide ayant une biodisponibilite amelioree
US20060052432A1 (en) Pharmaceutical compositions with improved dissolution
WO2004061433A1 (fr) Compositions pharmaceutiques a dissolution amelioree
CA2511881C (fr) Compositions pharmaceutiques comprenant un sel de sodium de celecoxib a dissolution amelioree
EP2339328A2 (fr) Compositions pharmaceutiques cocrystallisees de celecoxib
US6864373B2 (en) Stable amorphous celecoxib composite and process therefor
KR20050016596A (ko) 용해성이 개선된 약학 조성물
ZA200307576B (en) Orally deliverable pharmaceutical composition comprising an active compound having an aminosulfonyl group (Cox-2 inhibitor), a polyethylene glycol and a free-radical scavenging antioxidant.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref document number: 2006052432

Country of ref document: US

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 10528244

Country of ref document: US

122 Ep: pct application non-entry in european phase
WWP Wipo information: published in national office

Ref document number: 10528244

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP